Method for the preparation of phosphine butadiene ligands, complexes thereof with copper and use thereof in catalysis

ABSTRACT

The present invention relates to a method for preparing phosphine butadiene-type ligands, and their use, particularly as catalytic metal ligands used in the reactions leading to the formation of carbon-carbon and carbon-heteroatom bonds.

The present invention relates to a process for the preparation ofphosphorus-comprising ligands of butadienylphosphine type and to theirapplications, in particular as ligands for catalytic metals used inreactions for the formation of carbon-carbon and carbon-heteroatombonds.

Butadienyl phosphorus-comprising derivatives have been known since the1960s and are of interest in organic synthesis as a result of theirelectrophilic nature and their biological activity, in particularantiviral activity.

With the development of asymmetric synthesis, butadienylphosphorus-comprising derivatives today form the subject of intensiveresearch for their great importance in coordination chemistry by thepresence, in these derivatives, of two ligands much employed incoordination chemistry: the phosphine ligand and the butadiene ligand.

Processes for the synthesis of derivatives of butadienylphosphine typeare currently few in number. They generally employ sophisticatedstarting compounds and/or numerous synthetic stages, thus resulting inmediocre overall yields.

Thus, for example, M. D. Fryzuk et al. (J. Org. Chem., (1988), 53,4425-4426) disclose a process for the preparation ofbutadienylphosphines in two stages, the first stage consisting of ahydrozirconation of a conjugated enyne, thus rendering the processrelatively complex to carry out.

Z. Xi et al. (Tetrahedron Lett., (2004), 45, 2427-2429) also bring in analkyne as starting compound, which alkyne is reacted with a zirconiumcomplex.

M. P. Teulade and P. Savignac (Tetrahedron Lett., (1989), 30(46),6327-6330) provide a general synthesis of butadienylphosphines based ona Wittig-Horner reaction starting from cyclic phosphonates, and J. L.Cabioch and J. M. Denis (J. Organomet. Chem., (1989), 377(2-3), 227-233)provide, for their part, an example of the synthesis of an unsubstitutedprimary butadienylphosphine starting from the corresponding phosphonatein the presence of an aluminum salt.

Yet other syntheses have been described; however, all comprise a largenumber of stages, require starting materials which are expensive ordifficult to employ or to prepare, result in the desired products onlywith low yields or else do not make possible access to a great varietyof butadienylphosphines.

Consequently, a first objective of the present invention consists inproviding a synthetic route suited to the preparation of variedbutadienylphosphines, with acceptable yields, which is easy to use,advantageously with a minimum of stages, starting from startingcompounds which are relatively common or easy to prepare.

It has now been discovered that this first objective, and also otherswhich will become apparent during the description of the invention whichfollows, is achieved in all or at least in part by virtue of the processfor the preparation of butadienylphosphines set out below.

A subject matter of the present invention is first of all the processfor the preparation of a butadienylphosphine of formula (1):

in which formula:

-   -   R^(a) and R^(b), which are identical or different, preferably        identical, each represent a radical chosen independently from        alkyl, aryl, heteroaryl, monoalkylamino, dialkylamino, alkoxy,        aryloxy and heteroaryloxy;    -   R¹, R², R³, R⁴ and R⁵, which are identical or different, are        chosen independently from hydrogen, a hydrocarbon radical, an        aryl radical and a heteroaryl radical;        said process comprising the stages of:

a) bringing a phosphonium halide of formula (2) into contact with astrong base, in a polar aprotic solvent, for example tetrahydrofuran, atlow temperature, generally between −70° C. and 0° C., for example −50°C., to result in the phosphonium diylide (3):

where R¹ is as defined above, Z and Z′ have definitions identical tothose of R^(a) and R^(b) defined above and X represents a halogen atomchosen from fluorine, chlorine, bromine and iodine;

b) which diylide (3) is reacted, in a polar aprotic solvent medium, forexample tetrahydrofuran, at a temperature generally of between −70° C.and +10° C., for example −10° C., with a halophosphine (4):

where R^(a) and R^(b) are as defined above and X′ represents a halogenatom chosen from fluorine, chlorine, bromine and iodine;to result in the phosphonium ylide (5a), which undergoes a prototropicrearrangement to give the phosphonium ylide (5b):

where R^(a), R^(b), Z and Z′ are as defined above;

c) the ylide (5b) then being brought together, generally at atemperature of between 0° C. and 50° C., for example at ambienttemperature, in a polar aprotic solvent, such as tetrahydrofuran, withan α,β-unsaturated carbonyl derivative of formula (6):

in which R², R³, R⁴ and R⁵ are as defined above, to result, afterremoval of the solvent and optional purification, in thebutadienylphosphine (1).

In one embodiment, R⁴ and/or R⁵ can be connected so as to form, with thecarbon atom which carries them, a carbocyclic or heterocyclic grouphaving from 3 to 20 carbon atoms which is saturated, unsaturated,monocyclic or polycyclic, in the latter case comprising two or threerings, it being possible for the adjacent rings to be aromatic innature.

The process described above can advantageously be carried out in justone reactor (one pot), that is to say without it being necessary toisolate all or some of the intermediates. However, of course and ifdesired, it is possible to isolate one or more of the intermediates,advantageously when they are stable.

The strong base used for the preparation of the phosphonium diylide (3)described above is generally a metal base, that is to say a strong basecomprising one or more metals advantageously chosen from alkali metalsand alkaline earth metals, in particular from lithium, sodium,potassium, magnesium, calcium and barium. Strong lithium bases arepreferred, in particular butyllithium. In this case, the counterion ofthe phosphonium diylide (3) is the lithium cation.

In the present invention, the following terms have the meanings below,unless otherwise indicated:

-   -   “alkyl” represents a saturated linear or branched hydrocarbon        radical comprising from 1 to 10 carbon atoms, preferably from 1        to 6 carbon atoms, in particular the methyl radical, the ethyl        radical, the propyl radicals, the butyl radicals, the pentyl        radicals, the hexyl radicals, the heptyl radicals, the octyl        radicals, the nonyl radicals and the decyl radicals;    -   “aryl” represents a mono- or polycyclic aromatic hydrocarbon        radical, for example the phenyl radical and the naphthyl        radical;    -   “heteroaryl” represents a mono- or polycyclic aromatic        hydrocarbon radical additionally comprising one or more        identical or different heteroatoms chosen from nitrogen, oxygen        or sulfur, each of the rings comprising 5 or 6 members; examples        of heteroaryl radicals are the pyridyl radicals, the quinolyl        radicals, the imidazolyl radicals and the tetrazolyl radicals,        without this list constituting any limitation;    -   “hydrocarbon radical” as indicated for the R¹, R², R³, R⁴ and R⁵        radicals represents a linear, branched or cyclic (mono- or        polycyclic) hydrocarbon radical comprising from 1 to 20 carbon        atoms and being able to comprise one or more unsaturations in        the form of double and/or triple bond(s), for example, and        without implied limitation, methyl, ethyl, propyl, isopropyl,        butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl, benzyl,        phenyl, vinyl, allyl and others;    -   in the terms “alkoxy”, “aryloxy”, “heteroaryloxy”,        “monoalkylamino” and “dialkylamino”, the definitions of the        terms alkyl-, aryl- and heteroaryl- correspond to the generic        terms defined above.

All the radicals having the definitions appearing above can optionallybe substituted by one or more halogen atoms, advantageously chosen fromfluorine, chlorine, bromine and iodine, by one or more linear orbranched alkyl, alkenyl and/or alkynyl radicals comprising from 1 to 10carbon atoms, or by one or more hydroxyl, alkoxy, alkenyloxy,alkynyloxy, aryl, heteroaryl, amino, alkylamino, dialkylamino, carboxy,carbonyl, carbonylamino, carbonylalkylamino, carbonyldialkylaminoradicals, it being possible for the substituents to be identical ordifferent.

In the expanded formula of the compound of formula (1) shown above, thebonds in “wavy” lines indicate that the two double bonds can occur inthe cis or trans configuration, that is to say that thebutadienylphosphine of formula (1) can be of E or Z configuration.

The butadienylphosphines obtained according to the process of theinvention can be specifically of Z configuration (formula (1Z)) or of Econfiguration (formula (1E)) or in the form of a mixture in allproportions:

The E and Z isomers of the phosphines obtained according to the processof the present invention can be separated, if necessary, according toconventional methods or processes known to a person skilled in the art.

Depending on the applications envisaged, preference is given to thebutadienylphosphines of Z configuration or to the butadienylphosphinesof E configuration or else to the mixtures of the E and Zbutadienylphosphines in all proportions.

The process of the invention is particularly well suited to thepreparation of the butadienylphosphines of formula (1), of Z or Econfiguration, in which:

-   -   R^(a) and R^(b), which are identical or different, each        represent a radical chosen independently from alkyl, in        particular methyl, ethyl, propyl or butyl; aryl, in particular        phenyl or naphthyl; heteroaryl, in particular pyridyl or        quinolyl; and, preferably, R^(a) and R^(b) are identical and        each represent phenyl;    -   R¹ represents hydrogen or alkyl, in particular methyl, ethyl or        propyl; preferably, R¹ represents hydrogen;    -   R², R³ and R⁴, which are identical or different, are chosen        independently from hydrogen, an alkyl radical, an aryl radical        and a heteroaryl radical, in particular from hydrogen and an        alkyl radical, especially methyl, ethyl or propyl;    -   R⁵ is chosen from hydrogen, an alkyl radical, an aryl radical        and a heteroaryl radical; preferably, R⁵ represents alkyl, in        particular methyl, ethyl, propyl, butyl or pentyl, or also        represents phenyl, naphthyl, pyridyl or quinolyl.

The process of the invention makes it possible in particular to obtainthe butadienylphosphines (Z)-Ph(C₄H₄)PPh₂, (E)-Ph(C₄H₄)PPh₂, (Z)—CH₃(C₄H₄)PPh₂ and (E)-CH₃Ph(C₄H₄)PPh₂, where Ph represents phenyl.

The process described above makes it possible to obtain thebutadienylphosphines of formula (1) from compounds which are readilyavailable commercially or are easily prepared from procedures known fromthe literature. In addition, the low number of stages of the processmakes it easy to operate.

As indicated above, the process can advantageously be carried out injust one operation (one pot), that is to say without it being necessaryto isolate and/or to purify the synthetic intermediates. However, it ispossible to isolate and/or purify the intermediates, for example for thepurpose of studying the satisfactory progression of the reaction or itskinetics, of analyzing the intermediates formed, and others.

The butadienylphosphines of formula (1), the process of preparation ofwhich represents a first subject matter of the present invention, canentirely advantageously be used as ligands for copper in order to formcomplexes.

This is because butadienylphosphines are of great interest incoordination chemistry and in catalysis due to the fact that theycombine two ligands of great importance in organometallic chemistry:conjugated dienes and phosphines.

Such complexes of copper with at least one butadienylphosphine offormula (1) as defined supra constitute another subject matter of thepresent invention.

The complexes according to the invention can be representedschematically under the form Pho-Bu/Cu, where Pho-Bu represents abutadienylphosphine of formula (1) defined above and Cu represents acopper atom. This schematic representation does not in any way indicatethe number of moles of butadienylphosphine present, with respect to thenumber of copper atoms present.

The term “monomer complex” is used to describe a Pho-Bu/Cu complex whichcomprises one copper atom, the term “dimer complex” is used to describea Pho-Bu/Cu complex which comprises two copper atoms, the term “trimercomplex” is used to describe a Pho-Bu/Cu complex which comprises threecopper atoms, and the like.

The invention also relates to phenyl- ormethyl-butadienyldiphenylphosphine/copper iodide monomer complexes[Ph-CH═CH—CH═CH—PPh₂]₂CuI(iododi{η-[(4-phenyl-1,3-butadienyl)diphenylphosphine]}copper complex)and [CH₃—CH═CH—CH═CH—PPh₂]₂CuI(iododi{η-[(4-methyl-1,3-butadienyl)diphenylphosphine]}copper complex),where Ph represents the phenyl radical.

The Pho-Bu/Cu complexes defined above can be prepared according toconventional techniques known to a person skilled in the art. Forexample, the Pho-Bu/Cu complexes can be prepared by bringing at leastone butadienylphosphine, in particular of formula (1) defined supra,into contact with metallic copper or a copper (copper(I) or copper(II))derivative, for example a copper halide, such as cupric or cuprousiodide, bromide or chloride, or other derivatives, in particularorganocopper compounds, for example copper acetylacetonate.

The reaction is generally carried out under an inert atmosphere, forexample under nitrogen or argon, in an organic solvent medium,preferably a polar aprotic solvent, for example acetonitrile. Thecomplexing reaction is usually carried out at a temperature of between0° C. and 80° C., depending on the nature of the compounds present, andthe reaction temperature is generally ambient temperature.

The complex is generally obtained in the form of a precipitate which isisolated from the reaction medium according to techniques known per se,for example by filtration, and optionally recrystallization from asolvent, advantageously identical to that used for the complexingreaction.

According to an alternative form, the Pho-Bu/Cu complex canadvantageously be prepared in situ in the reaction medium for thereaction catalyzed by the Pho-Bu/Cu complex. Such an alternative form isillustrated in the arylation examples (examples C) which follow.

Because of their very great advantage in catalysis,copper/butadienylphosphine complexes, in particular those of Zconfiguration, are applied entirely appropriately as catalytic systemfor reactions for the creation of carbon-carbon (C—C) orcarbon-heteroatom (C-HE) bonds according to the “Ullmann process” (F.Ullmann and H. Kipper, Ber. Dtsch. Chem. Ges., 1095, 38, 2120-2126).

The copper-catalyzed Ullmann reaction is one of the most widely usedmethods industrially due to the attractive cost of copper, in comparisonwith the costs of other noble metals, such as palladium, ruthenium andothers.

Recently, Buchwald et al. (J. Am. Chem. Soc., 2001, 123, 7727-7729) haveprovided for the use of conventional copper ligands in carrying out thiscopper-catalyzed reaction. International patent applicationWO-A-03/101966 describes copper ligands which make possible a reactionof Ullmann type under mild conditions, with catalytic amounts of copper.These ligands are mainly ligands of oxime type which require a specificsynthesis and consequently result in relatively expensive reactionproducts.

Thus, another objective of the invention is to provide copper ligandswhich are easier to prepare and which result in lower reaction coststhan those generated to date for coupling reactions of Ullmann type. Asother objective, the present invention is targeted at obtainingsynthetic yields which are further improved, in comparison with theyields obtained with the processes known in the field.

According to another aspect, the present invention relates to a processfor the creation of a carbon-carbon (C—C) bond or of a carbon-heteroatom(C-HE) bond by reacting a compound carrying a leaving group with anucleophilic compound carrying a carbon atom or a heteroatom (HE)capable of replacing the leaving group, thus creating a C—C or C-HEbond, in which process the reaction is carried out in the presence of aneffective amount of a catalytic system comprising at least onecopper/butadienylphosphine complex.

The inventors have now discovered that catalytic systems based on coppercomplexed with a butadienylphosphine make it possible to bring about thecreation of a carbon-carbon (C—C) bond or of a carbon-heteroatom (C-HE)bond by reacting a compound carrying a leaving group with a nucleophiliccompound carrying a carbon atom or a heteroatom (HE) capable ofreplacing the leaving group, thus creating a C—C or C-HE bond.

The general scheme of the process according to the present invention canbe illustrated as follows:

in which:

-   -   Y—R⁰ represents a compound carrying a leaving group Y; and    -   R-Q: represents a nucleophilic compound, R being the residue of        said nucleophilic compound and Q being a carbon atom or a        heteroatom (HE) which can replace said leaving group Y.

According to a first alternative form of the process of the presentinvention, an arylation reaction is carried out by reacting an aromaticcompound carrying a leaving group with a nucleophilic compound.

According to another alternative form of the process of the invention, avinylation or alkynylation reaction is carried out by respectivelyreacting, with a nucleophilic compound, a compound comprising a doublebond or a triple bond in the α position with respect to a leaving group.

In the account which follows of the present invention, the term“arylation” is used in its broad sense, since the use is envisaged of anunsaturated compound carrying a leaving group which is either ofunsaturated aliphatic type or of carbocyclic or heterocyclic aromatictype.

“Nucleophilic compound” is understood to mean a hydrocarbon organiccompound, both acyclic and cyclic or polycyclic, the characteristic ofwhich is to comprise at least one atom carrying a free doublet, whichmay or may not comprise a charge, and preferably a nitrogen, oxygen,sulfur, boron or phosphorus atom, or comprises a carbon atom which candonate its electron pair.

As mentioned above, the nucleophilic compound comprises at least oneatom carrying a free doublet which can be contributed by a functionalgroup and/or a carbanion.

Mention may in particular be made, as functional groups and/orcarbanions comprising said at least one atom, of the following atoms andgroups:

According to another alternative form of the invention, the nucleophiliccompound comprises at least one nitrogen atom carrying a free doubletincluded in a saturated, unsaturated or aromatic ring; the ringgenerally comprises from 3 to 8 atoms.

It should be noted that, when the nucleophilic compound comprises afunctional group, examples of which are given above, which carries oneor more negative charges, said compound then occurs in a salified form.The counterion is generally a metal cation, such as an alkali metal,preferably lithium, sodium or potassium, or an alkaline earth metal,preferably calcium, or the residue of an organometallic compound, suchas, in particular, an organomagnesium or organozinc compound.

A first advantage of the process of the invention is to carry out thereaction at moderate temperature.

Another advantage is to be able to use a broad range of agents for thecoupling, in particular of agents for the arylation, of nucleophiles,not only iodides but also bromides, chlorides or triflates, inparticular aryl iodides, aryl bromides, aryl chlorides or aryltriflates.

Another advantage of the process of the invention is to resort tocatalysis via copper rather than palladium or nickel, that is to say acatalyst which is less toxic and which is additionally advantageous fromthe economic viewpoint.

The process of the invention concerns a large number of nucleophiliccompounds and examples are given below, by way of illustration, withoutany limiting nature.

A first category of substrates (nucleophilic compounds) to which theprocess of the invention applies comprises nitrogenous organicderivatives and more particularly primary or secondary amines; hydrazineor hydrazone derivatives; amides; sulfonamides; urea derivatives; orheterocyclic derivatives, preferably nitrogen-comprising and/orsulfur-comprising heterocyclic derivatives.

More specifically, the primary or secondary amines can be represented bythe general formula (Ia):

in which formula (Ia):R¹¹ and R¹², which are identical or different, are chosen from hydrogen,a hydrocarbon radical (1 to 20 carbon atoms, as defined above), an arylradical or a heteroaryl radical and from any sequence of two or more ofthe abovementioned groups, it being understood that at most one of theR¹¹ and R¹² groups represents a hydrogen atom.

The amines preferably employed correspond to the formula (Ia) in whichR¹¹ and R¹², which are identical or different, represent a C₁ to C₁₅,preferably C₁ to C₁₀, alkyl group, a C₃ to C₈, preferably C₅ or C₆,cycloalkyl group, or a C₆ to C₁₂ aryl or arylalkyl group.

Mention may be made, as more particular examples of R¹¹ and R¹² groups,of C₁ to C₄ alkyl, phenyl, naphthyl or benzyl groups.

Mention may be made, as more specific examples of amines of formula(Ia), of aniline, N-methylaniline, diphenylamine, benzylamine anddibenzylamine.

The present invention does not exclude the presence of one or moreunsaturations in the hydrocarbon chain(s), such as one or more doubleand/or triple bonds, which may be conjugated or nonconjugated.

The hydrocarbon chain(s) can also be interrupted by one or moreheteroatoms (for example, oxygen, sulfur, nitrogen or phosphorus) and/orby a nonreactive functional group, such as, for example, —CO—.

It should be noted that the amino group can be in the form of anions.The counterion is then a metal cation, preferably an alkali metal cationand more preferably sodium or potassium. Mention may be made, asexamples of such compounds, of sodium amide or potassium amide.

The hydrocarbon chain can optionally carry one or more substituents, asindicated above, in particular atoms, groups or radicals chosen fromhalogen, ester, amino, alkylphosphine and/or arylphosphine, insofar asthey do not interfere.

The saturated or unsaturated, linear or branched acyclic aliphaticgroups can optionally carry a cyclic substituent. The term “ring”denotes a saturated, unsaturated or aromatic carbocylic or heterocyclicring.

The acyclic aliphatic group can be connected to the ring via a valencebond, a heteroatom or a functional group, such as oxy, carbonyl,carboxyl, sulfonyl, and the like.

It is possible to envisage, as examples of cyclic substituents,cycloaliphatic, aromatic or heterocyclic substituents, in particularcycloaliphatic substituents comprising 6 carbon atoms in the ring orbenzene substituents, these cyclic substituents themselves optionallycarrying any substituent, insofar as they do not interfere with thereactions occurring in the process of the invention. Mention may inparticular be made of the alkyl or alkoxy groups comprising from 1 to 4carbon atoms.

Among the aliphatic groups carrying a cyclic substituent,cycloalkylalkyl groups, for example cyclohexylalkyl groups, or arylalkylgroups, preferably C₇ to C₁₂ arylalkyl groups, in particular benzyl orphenylethyl groups, are more particularly targeted.

In the general formula (Ia), the R¹¹ and R¹² groups can also represent,independently of one another, a saturated carbocyclic group or acarbocyclic group comprising one or two unsaturations in the ring,generally a C₃ to C₈ ring, preferably comprising 6 carbon atoms in thering; it being possible for said ring to be substituted. Mention may bemade, as preferred examples of groups of this type, of cyclohexyl groupswhich are optionally substituted, in particular by linear or branchedalkyl groups having from 1 to 4 carbon atoms.

The R¹¹ and R¹² groups can represent, independently of one another, anaromatic hydrocarbon group and in particular a benzene hydrocarbon groupcorresponding to the general formula (F₁):

in which:

-   -   t represents 0, 1, 2, 3, 4 or 5; and    -   W represents a group chosen from linear or branched C₁-C₆ alkyl,        linear or branched C₁-C₆ alkoxy, linear or branched C₁-C₆        alkylthio, —NO₂, —CN, halogen and CF₃.

The aromatic hydrocarbon group can thus be substituted. W illustratessome types of preferred substituents but the list is not limiting.

R¹¹ and R¹² can also represent, independently of one another, apolycyclic aromatic hydrocarbon group with the rings being able to form,with one another, ortho-fused or ortho- and peri-fused systems. Mentionmay more particularly be made of a naphthyl group, it being possible forsaid ring to be substituted.

R¹¹ and R¹² can also represent, independently of one another, apolycyclic hydrocarbon group composed of at least two saturated and/orunsaturated carbocycles or of at least two carbocycles, only one ofwhich is aromatic, which form, with one another, ortho- or ortho- andperi-fused systems. Generally, the rings are C₃ to C₈ rings, preferablyC₆ rings. Mention may be made, as more specific examples, of the bornylgroup or the tetrahydronaphthyl group.

R¹¹ and R¹² can also represent, independently of one another, asaturated, unsaturated or aromatic heterocyclic group comprising inparticular 5 or 6 atoms in the ring, including one or two heteroatoms,such as nitrogen atoms (unsubstituted by a hydrogen atom), sulfur atomsand oxygen atoms; it being possible for the carbon atoms of thisheterocycle also to be substituted.

R¹¹ and R¹² can also represent a polycyclic heterocyclic group definedas being either a group composed of at least two aromatic or nonaromaticheterocycles comprising at least one heteroatom in each ring andforming, with one another, ortho- or ortho- and peri-fused systems or agroup composed of at least one aromatic or nonaromatic hydrocarbon ringand at least one aromatic or nonaromatic heterocycle forming, with oneanother, ortho- or ortho- and peri-fused systems, it being possible forthe carbon atoms of said rings optionally to be substituted.

Mention may be made, as examples of R¹¹ and R¹² groups of heterocyclictype, inter alia, of the furyl, thienyl, isoxazolyl, furazanyl,isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyranyl or phosphinogroups and the quinolyl, naphthyridinyl, benzopyranyl or benzofuranylgroups.

The number of substituents present in each ring depends on the carbonfusion of the ring and on the presence or absence of unsaturation in thering. The maximum number of substituents capable of being carried by aring is easily determined by a person skilled in the art.

Other nucleophilic compounds capable of being employed in the process ofthe invention are, for example, the hydrazine derivatives correspondingto the formula (Ib):

in which:

-   -   R¹³ and R¹⁴, which are identical or different, have the meanings        given for R¹¹ and R¹² in the formula (Ia) and at most one of the        R³ and R⁴ groups represents a hydrogen atom.

The R¹³ and R¹⁴ groups more particularly represent a C₁ to C₁₅,preferably C₁ to C₁₀, alkyl group, a C₃ to C₈, preferably C₅ or C₆,cycloalkyl group, or a C₆ to C₁₂ aryl or arylalkyl group. Morepreferably, R¹³ and R¹⁴ represent a C₁ to C₄ alkyl, phenyl, benzyl ornaphthyl group.

Mention may be made, as other nucleophiles, of oximes andhydroxylamines, which can be represented by the general formulae (Ic)and (Id) respectively:

in which formulae:

-   -   R¹⁵ and R¹⁶, which are identical or different, have the        definitions given for R¹¹ and R¹² in the formula (Ia) and at        most one of the R¹⁵ and R¹⁶ groups represents a hydrogen atom;    -   R¹⁷ has the definitions given for R¹¹ or R¹² in the formula        (Ia), with the exception of the hydrogen atom; and    -   R¹⁸ is chosen from the hydrogen atom, a saturated or        unsaturated, linear or branched acyclic aliphatic group and a        saturated or unsaturated monocyclic or polycyclic carbocyclic        group, and from any sequence of two or more of said groups.

Preferred examples of oximes or hydroxylamines of formulae (Ic) and (Id)respectively are those for which R¹⁵, R¹⁶ and R¹⁷ represent C₁ to C₁₅,preferably C₁ to C₁₀, alkyl, C₃ to C₈, preferably C₅ or C₆, cycloalkylor C₆ to C₁₂ aryl or arylalkyl.

Mention may be made, as more particular examples of R¹⁵, R¹⁶ and R¹⁷groups, of C₁ to C₄ alkyl, phenyl, naphthyl or benzyl groups. Withregard to R¹⁸, it preferably represents C₁ to C₄ alkyl or benzyl.

According to another aspect, the present invention employs nucleophiliccompounds of hydrazine type which can be represented by the followingformula (Ie):

in which:

-   -   R¹⁹, R²⁰ and R²¹, which are identical or different, have the        definitions given for R¹¹ and R¹² in the formula (Ia);    -   R²¹ represents a hydrogen atom or a protective group G; and    -   at least one of the R¹⁹, R²⁰ and R²¹ groups does not represent a        hydrogen atom;    -   or else R¹⁹ and R²⁰ can together form, with the nitrogen atom        which carries them, a saturated, unsaturated or aromatic        monocyclic or polycyclic C₃-C₂₀ heterocyclic group.

Preferred hydrazines of formula (Ie) above are those in which R¹⁹ andR²⁰, which are identical or different, represent C₁-C₁₅, preferablyC₁-C₁₀ alkyl, C₃-C₈, preferably C₅ or C₆, cycloalkyl or C₆-C₁₂ aryl orarylalkyl. More preferably, the hydrazines are those of formula (Ie) inwhich R¹⁹ and R²⁰, which are identical or different, represent C₁ to C₄alkyl, phenyl, benzyl or naphthyl.

R¹⁹ and R²⁰ can be connected together, so as to form, with the nitrogenatom which carries them, a saturated, unsaturated or aromatic monocyclicor polycyclic C₃-C₂₀ heterocyclic group comprising two or threeortho-fused rings, that is to say at least two rings which have twocarbon atoms in common.

For the polycyclic compounds, the number of atoms of each ring canpreferably vary between 3 and 6. According to a preferred embodiment,R¹⁹ and R²⁰ together form a cyclohexane or fluorenone ring.

In the above formula (Ie), R²¹ preferably represents a hydrogen atom,alkyl (preferably C₁-C₁₂), alkenyl or alkynyl (preferably C₂-C₁₂),cycloalkyl (preferably C₃-C₁₂), or aryl or arylalkyl (preferablyC₆-C₁₂). More preferably, R²¹ represents a hydrogen atom or a C₁-C₄alkyl group.

It should be noted that, when the nucleophilic compound comprises an NH₂group, both hydrogen atoms can react. In such a case, and in order toincrease the selectivity of the reaction, one or both hydrogen atoms canadvantageously be masked by the use of a protective group. Suchprotective groups are well known in the field and mention may be made ofthe protective groups commonly used, such as, for example, acyl (acetyl,benzoyl), BOC (butoxycarbonyl), CBZ (carbobenzoxy), FMOC(trifluoromethyloxycarbonyl) or MSOC(2-(methane-sulfenyl)ethoxycarbonyl) groups. Reference may be made, onthis subject, for example, to the work by T. W. Greene et al.,Protective Groups in Organic Synthesis, 2^(nd) edition, John Wiley &Sons Inc., as regards the reactions for protecting and deprotectingamino groups.

Other nucleophilic compounds which can be employed in the process of thepresent invention are the compounds of hydrazone type, which can berepresented by the formula (If):

in which:

-   -   R²², R²³ and R²⁴, which are identical or different, have the        definitions given for R¹¹ and R¹² in the formula (Ia);    -   at most one of the R²² and R²³ groups represents the hydrogen        atom;    -   or else R²² and R²³ can together form, with the nitrogen atom        which carries them, a saturated, unsaturated or aromatic        monocyclic or polycyclic C₃-C₂₀ carbocyclic or heterocyclic        group.

Preferred examples of hydrazones of above formula (If) are those inwhich R²² and R²³, which are identical or different, represent C₁-C₁₅,preferably C₁-C₁₀, alkyl, C₃-C₈, preferably C₅ or C₆, cycloalkyl, orC₆-C₁₂ aryl or arylalkyl. More preferably, examples of hydrazones offormula (If) are those in which R²² and R²³, which are identical ordifferent, represent C₁ to C₄ alkyl, phenyl, benzyl or naphthyl.

R²² and R²³ can together form, with the nitrogen atom which carriesthem, a saturated, unsaturated or aromatic monocyclic or polycyclicC₃-C₂₀ carbocyclic or heterocyclic group comprising two or threeortho-fused rings.

For the polycyclic compounds, the number of atoms of each ring canpreferably vary between 3 and 6. According to a preferred embodiment,R²² and R²³ together form a cyclohexane or fluorenone ring.

In the above formula (If), R²⁴ preferably represents a hydrogen atom oran alkyl (preferably C₁-C₁₂), alkenyl or alkynyl (preferably C₂-C₁₂),cycloalkyl (preferably C₃-C₁₂), or aryl or arylalkyl (preferably C₆-C₁₂)group. More preferably, R²⁴ represents a hydrogen atom or a C₁-C₄ alkylgroup.

The invention is also targeted at the compounds of amide typecorresponding more particularly to the formula (Ig):

R²⁵—NH—CO—R²⁶  (Ig)

in which R²⁵ and R²⁶ have the meanings given for R¹¹ and R¹² in theformula (Ia).

Mention may be made, as examples of compounds of formula (Ig), ofoxazolidin-2-one, benzamide and acetamide.

The invention also applies to compounds of sulfonamide type which can,for example, correspond to the formula (Ih):

R²⁷—SO₂—NH—R²⁸  (Ih)

in which R²⁷ and R²⁸ have the meanings given for R¹¹ and R¹² in theformula (Ia).

Mention may be made, as example of compounds of formula (Ih), oftosylhydrazide.

Mention may be made, as other types of nucleophilic substrates, of ureaderivatives, such as guanidines, which can be represented by the formula(Ii):

in said formula (Ii), the R²⁹ groups, which are identical or different,have the meanings given for R¹¹ and R¹² in the formula (Ia).

Mention may be made, as example of compounds of formula (Ii), ofN,N,N′,N′-tetramethylguanidine.

Yet other examples of nucleophilic compounds which can be used in theprocess of the present invention comprise amino acids and theirderivatives, for example those corresponding to the following formula(Ij):

in which:

-   -   R_(AA) represents a hydrogen atom or the residue of an amino        acid, preferably a hydrogen atom; a linear or branched C₁-C₁₂        alkyl optionally carrying a functional group; a C₆-C₁₂ aryl or        arylalkyl; or a functional group, preferably a hydroxyl group;    -   R³⁰ and R³¹ have the definitions given for R¹¹ and R¹² in the        formula (Ia);    -   R_(h) represents a hydrogen atom, a metal cation, preferably an        alkali metal cation, or a C₁-C₁₂ hydrocarbon group, preferably a        C₁-C₁₂ alkyl group.

According to a preferred embodiment, R_(AA) in the above formula (Ij)represents alkyl, optionally comprising a functional group, for example—OH, —NH₂, —CO—NH₂, —NH—CNH—, —HN—C(O)—NH₂, —COOH, —SH or —S—CH₃, or animidazole, pyrrole or pyrazole group.

Examples of such amino acids comprise glycine, cysteine, aspartic acid,glutamic acid or histidine.

Nucleophilic substrates entirely well suited to the use of the processof the invention are the heterocyclic derivatives comprising at leastone nucleophilic atom, such as a nitrogen, sulfur or phosphorus atom.

More specifically, such compounds correspond to the general formula(Ik):

in said formula (Ik):

-   -   A symbolizes the residue of a ring forming all or part of an        aromatic or nonaromatic, monocyclic or polycyclic heterocyclic        system, one of the carbon atoms of which is replaced by at least        one nucleophilic atom, such as a nitrogen, sulfur or phosphorus        atom;    -   R³², which are identical or different, represent(s) the        substituent(s) of the ring;    -   n represents the number of substituents on the ring.

The invention applies in particular to the monocyclic heterocycliccompounds corresponding to the formula (Ik) in which A symbolizes asaturated, unsaturated or aromatic heterocycle comprising in particular5 or 6 atoms in the ring which can comprise from 1 or 3 heteroatoms,such as nitrogen, sulfur and oxygen atoms, at least one of which fromamong them is a nucleophilic atom, such as NH or S.

A can also represent a polycyclic heterocyclic compound defined as beingcomposed of at least two aromatic or nonaromatic heterocycles comprisingat least one heteroatom in each ring and forming, with one another,ortho- or ortho- and peri-fused systems or composed of at least onearomatic or nonaromatic carbocycle and at least one aromatic ornonaromatic heterocycle forming, with one another, ortho- or ortho- andperi-fused systems.

It is also possible to start from a substrate resulting from the linkingof a saturated, unsaturated or aromatic heterocycle, such as mentionedabove, and of a saturated, unsaturated or aromatic carbocycle.Carbocycle is preferably understood to mean a ring of cycloaliphatic oraromatic type having from 3 to 8 carbon atoms, preferably 6 carbonatoms.

It should be noted that the carbon atoms of the heterocycle canoptionally be substituted, in their entirety or for a portion of themonly, by R³² groups.

The number of substituents present on the ring depends on the number ofatoms in the ring and on the presence or absence of unsaturations in thering. The maximum number of substituents capable of being carried by aring is easily determined by a person skilled in the art.

In the formula (Ik), n is preferably 0, 1, 2, 3 or 4; more preferably, nis equal to 0 or 1.

Examples of substituents are given below but this list does not exhibita limiting nature.

The R³² group or groups, which are identical or different, preferablyrepresent one of the following groups:

-   -   a linear or branched C₁ to C₆, preferably C₁ to C₄, alkyl group,        such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,        sec-butyl or tert-butyl;    -   a linear or branched C₂ to C₆, preferably C₂ to C₄, alkenyl or        alkynyl group, such as vinyl or allyl;    -   a linear or branched C₁ to C₆, preferably C₁ to C₄, alkoxy or        thioether group, such as the methoxy, ethoxy, propoxy,        isopropoxy or butoxy groups, an alkenyloxy group, preferably an        allyloxy group, or a phenoxy group;    -   a cyclohexyl, phenyl or benzyl group;    -   a group or a functional group, such as hydroxyl, thiol,        carboxyl, ester, amide, formyl, acyl, aroyl, amide, urea,        isocyanate, thioisocyanate, nitrile, azide, nitro, sulfone,        sulfonic, halogen, pseudohalogen or trifluoromethyl.

The present invention applies very particularly to the compoundscorresponding to the formula (Ik) in which the R³² group or groups moreparticularly represent an alkyl or alkoxy group.

More particularly, the optionally substituted residue A represents oneof the following rings:

-   -   a monocyclic heterocycle comprising one or more heteroatoms:

-   -   a bicycle comprising a carbocycle and a heterocycle comprising        one or more heteroatoms:

-   -   a tricycle comprising at least one carbocycle or one heterocycle        comprising one or more heteroatoms:

As examples of heterocyclic compounds, it is preferable to use thosewhich correspond to the formula (Ik) in which A represents a ring suchas imidazole, pyrazole, triazole, pyrazine, oxadiazole, oxazole,tetrazole, indole, pyrrole, phthalazine, pyridazine or oxazolidine.

As regards the nucleophilic compounds capable of also being employed inthe process of the invention, mention may also be made of the compoundsof alcohol type or of thiol type which can be represented by thefollowing formula (Im):

R³³—Z  (Im)

in which formula (Im):

-   -   R³³ represents a hydrocarbon group having from 1 to 20 atoms and        has the meanings given for R¹¹ or R¹² in the formula (Ia); and    -   Z represents a group of OM¹ or SM¹ type, in which M¹ represents        a hydrogen atom or a metal cation, preferably an alkali metal        cation.

The preferred compounds correspond to the formula (Im) in which R³³represents a hydrocarbon group having from 1 to 20 carbon atoms whichcan be a saturated or unsaturated, linear or branched acyclic aliphaticgroup, a saturated, unsaturated or aromatic, monocyclic or polycycliccarbocyclic or heterocyclic group, or any sequence of two or more of theabovementioned groups.

More specifically, R³³ preferably represents a saturated, linear orbranched, acyclic aliphatic group preferably having from 1 to 12 carbonatoms and more preferably from 1 to 4 carbon atoms.

The invention does not exclude the presence of an unsaturation in thehydrocarbon chain, such as one or more double and/or triple bonds, whichcan be conjugated or nonconjugated.

As mentioned for R¹¹ defined in the formula (Ia), the hydrocarbon chaincan optionally be interrupted by a heteroatom or a functional group orcarry one or more substituents.

In the formula (Im), R³³ can also represent a saturated or unsaturatedcarbocyclic group preferably having 5 or 6 carbon atoms in the ring, asaturated or unsaturated heterocyclic group comprising in particular 5or 6 atoms in the ring, including 1 or 2 heteroatoms, such as nitrogen,sulfur, oxygen or phosphorus atoms, a monocyclic aromatic carbocyclic orheterocyclic group, preferably phenyl, pyridyl, furyl, pyranyl,thiophenyl, thienyl, phospholyl, pyrazolyl, imidazolyl or pyrrolyl, or afused or nonfused polycyclic aromatic carbocyclic or heterocyclic group,preferably naphtyl.

Provided that R³³ comprises a ring, the latter can also be substituted.The substituent can have any nature insofar as it does not interferewith the main reaction. The number of substituents is generally at most4 per ring but is most often equal to 1 or 2. Reference may be made tothe definition of R³² in the formula (Ik).

The invention is also targeted at the case where R³³ comprises asequence of aliphatic and/or cyclic, carbocyclic and/or heterocyclicgroups.

An acyclic aliphatic group can be connected to a ring via a valencebond, a heteroatom or a functional group, such as oxy, carbonyl,carboxy, sulfonyl, and the like.

A more particular target is cycloalkylalkyl, for examplecyclohexylalkyl, groups or aralkyl groups having from 7 to 12 carbonatoms, in particular benzyl or phenylethyl groups.

The invention is also targeted at a sequence of carbocyclic and/orheterocyclic groups and more particularly a sequence of phenyl groupsseparated by a valence bond or an atom or functional group, such asoxygen, sulfur, sulfo, sulfonyl, carbonyl, carbonyloxy, imino,carbonylimino, hydrazo, or (C₁-C₁₀, preferably C₁-C₆)alkylenediimino.

The saturated or unsaturated, linear or branched acyclic aliphatic groupcan optionally carry a cyclic substituent. “Ring” is understood to meana saturated, unsaturated or aromatic carbocyclic or heterocyclic ring.

The preferred compounds of formula (Im) correspond more particularly tothe general formula (Im₁):

in which:

-   -   D symbolizes the residue of a monocyclic or polycyclic aromatic        carbocyclic group or a divalent group composed of any sequence        of two or more monocyclic aromatic carbocyclic groups;    -   R³⁴ represents one or more identical or different substituents;    -   Z represents a group of OM¹ or SM¹ type in which M¹ represents a        hydrogen atom or a metal cation, preferably an alkali metal        cation; and    -   n′ represents 0, 1, 2, 3, 4 or 5.

Reference may be made, as examples of R³⁴ substituents, to thoseidentified under R³² defined in the formula (Ik).

Use is more particularly made, among the compounds of formula (Im₁), ofthose for which the (D) residue represents:

-   -   a monocyclic or polycyclic aromatic carbocyclic group with rings        which can form, with one another, an ortho-fused system        corresponding to the formula (F₁₁):

-   -   in said formula (F₁₁), m represents a number equal to 0, 1 or 2,        the R³⁴ and n′ symbols, which are identical or different, having        the meanings given above;    -   a group composed of a sequence of two or more monocyclic        aromatic carbocyclic groups corresponding to the formula (F₁₂):

-   -   in said formula (F₁₂), the R³⁴ and n′ symbols, which are        identical or different, have the meanings given above, p is a        number equal to 0, 1, 2 or 3 and W represents a valence bond, a        C₁ to C₄ alkylene or alkylidene group, preferably a methylene or        isopropylidene group, or a functional group, such as oxy,        carbonyl, carboxy, sulfonyl and others.

The compounds of formula (Im) employed preferably correspond to theformulae (F₁₁) and (F₁₂), in which:

-   -   R³⁴ represents a hydrogen atom, a hydroxyl group, a —CHO group,        an —NO₂ group or a linear or branched alkyl or alkoxy group        having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon        atoms, more preferably methyl, ethyl, methoxy or ethoxy;    -   W symbolizes a valence bond, an alkylene or alkylidene group        having from 1 to 4 carbon atoms, or an oxygen atom;    -   m is equal to 0 or 1;    -   n′ is equal to 0, 1 or 2; and    -   p is equal to 0 or 1.

Mention may more particularly be made, by way of illustration ofcompounds corresponding to the formula (Im), of:

-   -   those in which the D residue corresponds to the formula (F₁₁) in        which m and n′ are equal to 0, such as phenol or thiophenol;    -   those in which the D residue corresponds to the formula (F₁₁) in        which m is equal to 0 and n′ is equal to 1, such as        hydroquinone, pyrocatechol, resorcinol, alkylphenols,        alkylthiophenols, alkoxyphenols, salicyl aldehyde,        para-hydroxy-benzaldehyde, methyl salicylate, the methyl ester        of para-hydroxybenzoic acid, chlorophenols, nitrophenols or        para-acetamidophenol;    -   those in which the D residue corresponds to the formula (F₁₁) in        which m is equal to 0 and n′ is equal to 2, such as        dialkylphenols, vanillin, isovanillin,        2-hydroxy-5-acetamidobenzaldehyde,        2-hydroxy-5-propionamidobenzaldehyde, 4-allyloxy-benzaldehyde,        dichlorophenols, methylhydroquinone or chlorohydroquinone;    -   those in which the D residue corresponds to the formula (F₁₁) in        which m is equal to 0 and n′ is equal to 3, such as        4-bromovanillin, 4-hydroxy-vanillin, trialkylphenols,        2,4,6-trinitrophenol, 2,6-dichloro-4-nitrophenol,        trichlorophenols, dichlorohydroquinones or        3,5-dimethoxy-4-hydroxy-benzaldehyde;    -   those in which the D residue corresponds to the formula (F₁₁) in        which m is equal to 1 and n′ is greater than or equal to 1, such        as dihydroxy-naphthalene, 4-methoxynaphth-1-ol or        6-bromo-naphth-2-ol;    -   those in which the D residue corresponds to the formula (F₁₂) in        which p is equal to 1 and n′ is greater than or equal to 1, such        as 2-phenoxy-phenol, 3-phenoxyphenol, phenylhydroquinone,        4,4′-dihydroxybiphenyl, 4,4′-isopropylidenediphenol (bisphenol        A), bis(4-hydroxyphenyl)methane, bis(4-hydroxyphenyl) sulfone,        bis(4-hydroxyphenyl) sulfoxide or tetrabromobisphenol A.

Mention may be made, among the other nucleophilic compounds belonging tocompletely different families which are capable of being employed in theprocess of the invention, of the compounds comprising phosphorus and thecompounds comprising phosphorus and nitrogen, preferably thosecorresponding to the following formulae:

phosphides of formula (R³⁵)₂—P⁻  (In);

phosphines of formula (R³⁵)₃—P  (Io);

phosphonium azayldiides of formula (R³⁵)₃—P⁺—N²⁻  (Ip);

phosphonium azaylides of formula (R³⁵)₃—P⁺—NR³⁶  (Iq);

in which formulae (In) to (Iq), the R³⁵ groups, which are identical ordifferent, and the R³⁶ group represent:

-   -   C₁-C₁₂ alkyl;    -   C₅-C₆ cycloalkyl;    -   C₅-C₆ cycloalkyl substituted by one or more C₁-C₄ alkyl groups        or C₁-C₄ alkoxy groups;    -   phenylalkyl, the aliphatic part of which has from 1 to 6 carbon        atoms;    -   phenyl; or    -   phenyl substituted by one or more C₁-C₄ alkyl groups or C₁-C₄        alkoxy groups or by one or more halogen atom(s).

Mention may be made, as particularly preferred phosphorus-comprisingcompounds, of tricyclohexyl-phosphine, trimethylphosphine,triethylphosphine, tri(n-butyl)phosphine, tri(isobutyl)phosphine,tri(tert-butyl)phosphine, tribenzylphosphine,dicyclohexylphenylphosphine, triphenylphosphine,dimethylphenylphosphine, diethylphenylphosphine ordi(tert-butyl)phenylphosphine.

Other compounds capable of being used in the process of the inventionare the hydrocarbon derivatives comprising a nucleophilic carbon.

Mention may more particularly be made of the anions of malonate typecomprising a —OOC—HC⁻—COO— group.

Mention may be made of the anions of alkyl malonate type of formula(Ir):

R³⁷—OOC—HC⁻(R³⁸)—COO—R′³⁷  (Ir)

in which:

-   -   R³⁷ and R′³⁷, which are identical or different, represent an        alkyl group comprising from 1 to 12 atoms, preferably from 1 to        4 atoms;    -   R³⁸ is chosen from a hydrogen atom; C₁-C₁₂ alkyl; C₅-C₆        cycloalkyl; C₅-C₆ cycloalkyl substituted by one or more C₁-C₄        alkyls or C₁-C₄ alkoxys; phenyl; phenyl substituted by one or        more C₁-C₄ alkyls or C₁-C₄ alkoxys or by one or more halogen        atoms; or phenylalkyl, the aliphatic part of which comprises        from 1 to 6 carbon atoms.

Mention may also be made of the anions of malononitrile andmalonodinitrile type comprising an R³⁷—OOC—HC⁻(R³⁸)—CN or NC—HC⁻—CNgroup respectively, in which R³⁷ and R³⁸ have the meanings given above.

The compounds of nitrile type comprising an R′²⁸—CN group, in which R′²⁸has any nature and has the meanings given for R¹¹ in the formula (Ia)and also represents a metal cation, preferably an alkali metal cation,more preferably still lithium, sodium or potassium, are also suitable.

Mention may be made, as examples of nitriles, of acetonitrile,cyanobenzene, optionally carrying one or more substituents on thebenzene ring, or ethanal cyanohydrin CH₃CH(OH)CN.

Also capable of being employed in the process of the invention are thecompounds of acetylenide type, which can be represented schematically bythe formula (Is):

R³⁹—C≡C⁻  (Is)

in said formula, R³⁹ has any nature and has in particular the meaningsgiven for R¹¹ in the formula (Ia) and the counterion is a metal cation,preferably sodium or potassium.

Mention may be made, as more specific examples, of sodium acetylide,potassium acetylide, sodium diacetylide or potassium diacetylide.

Mention may be made, as other categories of nucleophilic compounds whichcan be employed in the process of the invention, of the compounds ofprofen type and their derivatives, which can be represented by thefollowing formula (It):

R⁴⁰—HC⁻—COO—R⁴¹  (It)

in which formula:

-   -   R⁴⁰ has the meanings given for R¹¹ in the formula (Ia); and    -   R⁴¹ represents an alkyl group having from 1 to 12 carbon atoms,        preferably from 1 to 4 atoms.

The preferred compounds are those which correspond to the formula (It)in which R⁴⁰ represents an alkyl group having from 1 to 12 carbon atoms,a cycloalkyl group having 5 or 6 carbon atoms and an aryl group having 6or 12 carbon atoms, or a nitrogenous heterocycle having 5 or 6 atoms.

Mention may also be made, as nucleophilic compounds, of those comprisinga carbanion and for which the counterion is a metal, corresponding tothe following formulae:

in which:

-   -   the R⁴² group represents:    -   an alkyl group having from 1 to 12 carbon atoms;    -   a cycloalkyl group having 5 or 6 carbon atoms;    -   a cycloalkyl group having 5 or 6 carbon atoms substituted by one        or more alkyl radicals having 1 to carbon atoms and/or one or        more alkoxy radicals having from 1 or 4 carbon atoms;    -   a phenylalkyl group, the aliphatic part of which comprises from        1 to 6 carbon atoms;    -   a phenyl group;    -   a phenyl group substituted by one or more alkyl radicals having        from 1 to 4 carbon atoms or one or more alkoxy radicals having        from 1 to 4 carbon atoms or by one or more halogen atoms; or    -   a saturated, unsaturated or aromatic heterocyclic group        preferably comprising 5 or 6 atoms and comprising, as        heteroatom(s), sulfur, oxygen or nitrogen;    -   the R′⁴² and R″⁴² groups represent a hydrogen atom or a group        such as R⁴²;    -   two of the R⁴², R′⁴² and R″⁴² groups can be connected together        to form a saturated, unsaturated or aromatic carbocycle or        heterocycle preferably having 5 or 6 carbon atoms;    -   M₂ represents a metal element from Group Ia of the Periodic        Table of the Elements;    -   M₃ represents a metal element from Groups IIa and IIb of the        Periodic Table of the Elements;    -   X₁ represents a chlorine or bromine atom;    -   v is the valency of the metal M₃; and    -   w is equal to 0 or 1.

In the present text, reference is made, above and in the continuation,to the Periodic Table of the Elements published in the Bulletin de laSociété Chimique de France, No. 1 (1966).

Among the compounds of formulae (Iu₁) to (Iu₃), those which arepreferred involve, as metals, lithium, sodium, magnesium or zinc and X₁represents a chlorine atom.

The R⁴², R′⁴² and R″⁴² groups are advantageously a C₁-C₄ alkyl group, acyclohexyl group or a phenyl group or said groups can form a benzene,cyclopentadiene, pyridine or thiophene ring.

Mention may be made, as examples, of n-butyllithium, t-butyllithium,phenyllithium, methyl- or ethyl- or phenylmagnesium bromide or chloride,diphenylmagnesium, dimethyl- or diethylzinc, cyclopentadienylzinc, orethylzinc chloride or bromide.

Recourse may be had, as other nucleophilic compounds capable of beingemployed, to boronic acids or their derivatives and more particularly tothose corresponding to the following formula (Iv):

in which:

-   -   R⁴³ represents a monocyclic or polycyclic aromatic carbocyclic        or heterocyclic group; and    -   T¹ and T², which are identical or different, represent a        hydrogen atom, a saturated or unsaturated, linear or branched        aliphatic group having from 1 to 20 carbon atoms or an R⁴³        group.

More specifically, the boronic acid or its derivative corresponds to theformula (Iv) in which the R⁴³ group represents an aromatic carbocyclicor heterocyclic group. Thus, R⁴³ can take the meanings given above for Din the formula (Im₁). However, R⁴³ more particularly represents acarbocyclic group, such as a phenyl or naphthyl group, or a heterocyclicgroup, such as a pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,1,3-thiazolyl, 1,3,4-thiadiazolyl or thienyl group.

The aromatic ring can also be substituted. The number of substituents isgenerally at most 4 per ring but is most often equal to 1 or 2.Reference may be made to the definition of R³² of the formula (Ik) forexamples of substituents.

The preferred substituents are alkyl or alkoxy groups having from 1 to 4carbon atoms, an amino group, a nitro group, a cyano group, a halogenatom or a trifluoromethyl group.

As regards T¹ and T², which can be identical or different, they moreparticularly represent a hydrogen atom or a linear or branched acyclicaliphatic group which has from 1 to 20 carbon atoms and which issaturated or comprises one or more unsaturations in the form of doubleand/or triple bond(s) in the chain, preferably from 1 to 3unsaturations, which are preferably simple or conjugated double bonds.

T¹ and T² preferably represent an alkyl group having from 1 to 10 carbonatoms, preferably from 1 to 4 carbon atoms, or an alkenyl group havingfrom 2 to 10 carbon atoms, preferably a vinyl or 1-methylvinyl group.

T¹ and T² can additionally take the meanings given for R⁴³ and inparticular any ring can also carry a substituent as described above.

R⁴³ preferably represents a phenyl group.

It will not be departing from the scope of the present invention toresort to boronic acid derivatives, such as anhydrides and esters, moreparticularly alkyl esters having from 1 to 4 carbon atoms.

Mention may in particular be made, as examples of arylboronic acids, ofbenzeneboronic acid, 2-thiopheneboronic acid, 3-thiopheneboronic acid,4-methylbenzeneboronic acid, 3-methylthiophene-2-boronic acid,3-aminobenzeneboronic acid, 3-aminobenzeneboronic acid hemisulfate,3-fluorobenzeneboronic acid, 4-fluorobenzeneboronic acid,2-formylbenzeneboronic acid, 3-formylbenzeneboronic acid,4-formylbenzeneboronic acid, 2-methoxybenzeneboronic acid,3-methoxybenzeneboronic acid, 4-methoxybenzeneboronic acid,4-chlorobenzeneboronic acid, 5-chlorothiophene-2-boronic acid,benzo[b]furan-2-boronic acid, 4-carboxybenzeneboronic acid,2,4,6-trimethylbenzeneboronic acid, 3-nitrobenzeneboronic acid,4-(methyl-thio)benzeneboronic acid, 1-naphthaleneboronic acid,2-naphthaleneboronic acid, 2-methoxy-1-naphthaleneboronic acid,3-chloro-4-fluorobenzeneboronic acid, 3-acetamidobenzeneboronic acid,3-trifluoromethylbenzeneboronic acid, 4-trifluoromethylbenzeneboronicacid, 2,4-dichlorobenzeneboronic acid, 3,5-dichlorobenzeneboronic acid,3,5-bis(trifluoromethyl)benzeneboronic acid, 4,4′-biphenyldiboronic acidand the esters and anhydrides of these acids.

The present description provides lists of nucleophilic compounds but arenot under any circumstances limiting and any type of nucleophiliccompound can be envisaged.

As indicated above and according to the process of the presentinvention, a —C—C— or —C-HE- bond (where HE represents O, S, P, N, Si, Band others) can be created by reaction of a nucleophilic compound, suchas those which have just been described above, with a compound carryinga leaving group, in particular a compound comprising an unsaturated bondsituated in the α position with respect to a leaving group.

More specifically, the compound carrying a leaving group is representedby the general formula (II):

Y—R⁰  (II)

in which formula R⁰ represents a hydrocarbon group comprising from 2 to20 carbon atoms and optionally has at least one unsaturation (a doubleor triple bond) situated in the α position with respect to a leavinggroup Y or represents a monocyclic or polycyclic aromatic carbocyclicand/or heterocyclic group.

In accordance with the process of the invention, the compound of formula(I) is reacted with a compound of formula (II) in which:

-   -   R⁰ represents an aliphatic hydrocarbon group optionally        comprising a double bond and/or a triple bond in the α position        with respect to the leaving group or a cyclic hydrocarbon group        comprising an unsaturation carrying the leaving group; or    -   R⁰ represents a monocyclic or polycyclic aromatic carbocyclic        and/or heterocyclic group;    -   Y represents a leaving group, preferably a halogen atom or a        sulfonic ester group of formula —OSO₂—R^(e), in which R^(e) is a        hydrocarbon group.

The compound of formula (II) will be subsequently denoted by “compoundcarrying a leaving group”.

In the formula of the sulfonic ester group, R^(e) is a hydrocarbon groupof any nature. However, given that Y is a leaving group, it isadvantageous from an economic viewpoint for R^(e) to be simple in natureand to more particularly represent a linear or branched alkyl grouphaving from 1 to 4 carbon atoms, preferably a methyl or ethyl group;however, it can also represent, for example, a phenyl or tolyl group ora trifluoromethyl group.

Among the Y groups, the preferred group is a triflate group, whichcorresponds to an R^(e) group representing a trifluoromethyl group.

The choice is preferably made, as preferred leaving groups, of a bromineor chlorine atom.

The compounds of formula (II) very particularly targeted according tothe process of the invention can be categorized into three groups:

-   -   (1) the compounds of aliphatic type carrying a double bond and        which can be represented by the formula (IIa):

in which:

-   -   R⁴⁴, R⁴⁵ and R⁴⁶, which are identical or different, represent a        hydrogen atom or a hydrocarbon group having from 1 to 20 carbon        atoms which can be a saturated or unsaturated, linear or        branched aliphatic group, a saturated, unsaturated or aromatic,        monocyclic or polycyclic carbocyclic or heterocyclic group, or        any sequence of aliphatic and/or carbocyclic and/or heterocyclic        group(s) as mentioned above; and    -   Y symbolizes the leaving group as defined above;    -   (2) compounds of aliphatic type carrying a triple bond and which        can be represented by the formula (IIb):

R⁴⁴—C≡C—Y  (In)

in which:

-   -   R⁴⁴ has the meanings given in the formula (IIa); and    -   Y represents a leaving group as defined above;    -   (3) compounds of aromatic type which are subsequently denoted by        “halogenoaromatic compound” and which can be represented by the        formula (IIc):

in which:

-   -   E symbolizes the residue of a ring forming all or part of a        monocyclic or polycyclic aromatic carbocyclic and/or        heterocyclic system;    -   R⁴⁷, which are identical or different, represent substituents on        the ring;    -   Y represents a leaving group as defined above; and    -   n″ represents the number of substituents on the ring.

The invention applies to the unsaturated compounds corresponding to theformulae (IIa) and (IIb) in which R⁴⁴ preferably represents a saturated,linear or branched acyclic aliphatic group preferably having from 1 to12 carbon atoms.

The invention does not rule out the presence of another unsaturated bondin the hydrocarbon chain, such as a triple bond or else one or moredouble bonds, which can be conjugated or nonconjugated.

The hydrocarbon chain can optionally be interrupted by a heteroatom (forexample oxygen or sulfur) or by a functional group, insofar as thelatter does not react, and mention may be made in particular of a groupsuch as especially —CO—.

The hydrocarbon chain can optionally carry one or more substituentsinsofar as they do not react under the reaction conditions and mentionmay in particular be made of a halogen atom, a nitrile group or atrifluoromethyl group.

The saturated or unsaturated, linear or branched acyclic aliphatic groupcan optionally carry a cyclic substituent. “Ring” is understood to meana saturated, unsaturated or aromatic carbocyclic or heterocyclic ring.

The acyclic aliphatic group can be connected to the ring via a valencebond, a heteroatom or a functional group, such as oxy, carbonyl,carboxy, sulfonyl, and the like.

It is possible to envisage, as examples of cyclic substituents,cycloaliphatic, aromatic or heterocyclic substituents, in particularcycloaliphatic substituents comprising 6 carbon atoms in the ring, orbenzenic substituents, these cyclic substituents themselves optionallycarrying any substituent, insofar as they do not interfere in thereactions occurring in the process of the invention. Mention may inparticular be made of alkyl or alkoxy groups having from 1 to 4 carbonatoms.

Among aliphatic groups carrying a cyclic substituent, the aralkyl groupshaving from 7 to 12 carbon atoms, in particular the benzyl orphenylethyl groups, are more particularly targeted.

In the formulae (IIa) and (IIb), R⁴⁴ can also represent a saturated orunsaturated carbocyclic group preferably having 5 or 6 carbon atoms inthe ring, preferably a cyclohexyl group, a saturated or unsaturatedheterocyclic group comprising in particular 5 or 6 atoms in the ring,including one or two heteroatoms, such as nitrogen, sulfur and oxygenatoms, a monocyclic aromatic carbocyclic group, preferably a phenylgroup, or a fused or nonfused polycyclic aromatic carbocyclic group,preferably a naphthyl group.

With regard to R⁴⁵ and R⁴⁶, they preferably represent a hydrogen atom oran alkyl group having from 1 to 12 carbon atoms, a phenyl group or anaralkyl group having from 7 to 12 carbon atoms, preferably a benzylgroup.

In the formulae (IIa) and/or (IIb), R⁴⁴, R⁴⁵ and R⁴⁶ more particularlyrepresent a hydrogen atom or else R⁴⁴ represents a phenyl group and R⁴⁵and R⁴⁶ represent a hydrogen atom.

It should be noted that R³⁴ and R³⁵ can also represent a functionalgroup, insofar as they do not interact in the coupling reaction. Mentionmay be made, as examples of such functional groups, of the amido, ester,ether or cyano groups.

Mention may in particular be made, as examples of compoundscorresponding to the formulae (IIa) and (IIb), of vinyl chloride orvinyl bromide, or β-bromostyrene or β-chlorostyrene, or bromoalkyne oriodoalkyne.

The invention applies in particular to the halogenoaromatic compoundscorresponding to the formula (IIc) in which E is the residue of anoptionally substituted cyclic compound preferably having at least 4atoms in the ring, preferably 5 or 6 atoms, and representing at leastone of the following rings:

-   -   a monocyclic or polycyclic aromatic carbocycle, that is to say a        compound composed of at least two aromatic carbocycles which        form, with one another, ortho- or ortho- and peri-fused systems        or a compound composed of at least two carbocycles, only one of        which among them is aromatic, which form, with one another,        ortho- or ortho- and peri-fused systems;    -   a monocyclic aromatic heterocycle comprising at least one of the        heteroatoms P, O, N and/or S or a polycyclic aromatic        heterocycle, that is to say a compound composed of at least two        heterocycles comprising at least one heteroatom in each ring, at        least one of the two rings of which is aromatic, which form,        with one another, ortho- or ortho- and peri-fused systems, or a        compound composed of at least one carbocycle and at least one        heterocycle, at least one of the rings of which is aromatic,        which form, with one another, ortho- or ortho- and peri-fused        systems.

More particularly, the optionally substituted residue E preferablyrepresents the residue of an aromatic carbocycle, such as benzene, of anaromatic bicycle comprising two aromatic carbocycles, such asnaphthalene, or of a partially aromatic bicycle comprising twocarbocycles, one of the two of which is aromatic, such as1,2,3,4-tetrahydronaphthalene.

The invention also envisages the fact that E can represent the residueof a heterocycle insofar as it is more electrophilic than the compoundcorresponding to the formula (Ik).

Mention may be made, as specific examples, of an aromatic heterocycle,such as furan or pyridine, an aromatic bicycle comprising an aromaticcarbocycle and an aromatic heterocycle, such as benzofuran orbenzopyridine, a partially aromatic bicycle comprising an aromaticcarbocycle and a heterocycle, such as methylenedioxybenzene, an aromaticbicycle comprising two aromatic heterocycles, such as1,8-naphthylpyridine, or a partially aromatic bicycle comprising acarbocycle and an aromatic heterocycle, such as5,6,7,8-tetrahydroquinoline.

In the process of the invention, use is preferably made of ahalogenoaromatic compound of formula (IIc) in which E represents anaromatic nucleus, preferably a benzenic or naphthalenic nucleus.

The aromatic compound of formula (IIc) can carry one or moresubstituents.

In the present text, “more” is understood to mean generally less thanfour R⁴⁷ substituents on an aromatic nucleus. Reference may be made tothe definitions of the R⁴² group in the formula (Ik) for variousexamples of substituents.

R⁴⁷ can also represent a saturated, unsaturated or aromatic heterocyclecomprising 5 or 6 atoms and comprising sulfur, oxygen and/or nitrogen asheteroatom(s). In this respect, mention may in particular be made of thepyrazolyl or imidazolyl groups.

In the formula (IIc), n″ is equal to 0, 1, 2, 3 or 4, preferably equalto 1 or 2.

Mention may in particular be made, as examples of compoundscorresponding to the formula (IIc), of para-chlorotoluene,para-bromoanisole or para-bromo-trifluorobenzene.

The amount of the compound carrying a leaving group of formula (II),preferably of formula (IIa) or (Iib) or (IIc), employed is generallyexpressed with respect to the amount of nucleophilic compound and canvary within wide proportions; generally, it is in the vicinity ofstoichiometry.

Thus, the ratio of the number of moles of the compound carrying theleaving group to the number of moles of the nucleophilic compoundgenerally varies between 0.1 and 2.0, preferably between 0.5 and 1.5,more preferably between 0.8 and 1.2 and more preferentially between 0.9and 1.1.

In accordance with the process of the invention, the nucleophiliccompound, preferably corresponding to the formulae (Ia) to (Iv), isreacted with a compound carrying a leaving group, preferablycorresponding to the formula (II), more preferably to the formulae (IIa)or (IIb) or (IIc), in the presence of an effective amount of a catalyticsystem comprising a copper/butadienylphosphine complex as definedaccording to the invention.

This is because it has been discovered that it is possible to carry outcoupling reactions, such as defined supra, between nucleophiliccompounds and compounds carrying a leaving group by using a catalyticsystem comprising a copper/butadienylphosphine complex as definedaccording to the invention.

Mention may be made, as examples of catalytic systems capable of beingemployed, of those comprising at least one copper/butadienylphosphinecomplex, such as those defined supra under the generic term Pho-Bu/Cu,that is to say complexes of copper with at least one butadienylphosphineof formula (1) according to the invention.

Mention may be made, as example of complex of Pho-Bu/Cu typeparticularly suitable for the coupling reactions defined above, of thephenylbutadienyldiphenylphosphine/copper iodide monomer complex[Ph-CH═CH—CH═CH—PPh₂]₂CuI, where Ph represents the phenyl radical. Asalso indicated above, the Pho-Bu/Cu complex can be prepared in situ, inthe reaction medium for the coupling reaction.

The total amount of copper/butadienylphosphine complex catalyst employedin the process of the invention, expressed by the molar ratio of thenumber of moles of complex, expressed as copper, to the number of molesof compound carrying a leaving group, generally varies between 0.001 and0.5, preferably between 0.01 and 0.1.

According to an alternative form, the invention does not exclude thecopper being combined with a small amount of another metal elementdenoted by M. The metal element M is chosen from Group VIII, Ib and IIbof the Periodic Table of the Elements, as defined above.

Mention may be made, as examples of metals M, of silver, palladium,cobalt, nickel, iron and/or zinc.

Use is advantageously made of a mixture comprising palladium and copper.The palladium can be introduced in the form of a finely divided metal orin the form of an inorganic derivative, such as an oxide or a hydroxide.It is possible to resort to an inorganic salt, preferably nitrate,sulfate, oxysulfate, halide, oxyhalide, silicate or carbonate, or to anorganic derivative, preferably cyanide, oxalate, acetylacetonate,alkoxide, more preferably still methoxide or ethoxide, or carboxylate,more preferably still acetate.

It is also possible to employ complexes, in particular chlorine- orcyanide-comprising complexes, of palladium and/or of alkali metals,preferably sodium or potassium, or of ammonium. Mention may inparticular be made, as examples of compounds capable of being employedin the preparation of the catalysts of the invention, of palladium(II)bromide, palladium(II) chloride, palladium(II) iodide, palladium(II)cyanide, palladium(II) nitrate hydrate, palladium(II) oxide,palladium(II) sulfate dihydrate, palladium(II) acetate, palladium(II)propionate, palladium(II) butyrate or palladium benzoate.

Mention may be made, as specific examples of nickel derivatives, ofnickel(II) halides, such as nickel(II) chloride, bromide or iodide,nickel(II) sulfate, nickel(II) carbonate, salts of organic acidscomprising from 1 to 18 carbon atoms, such as, in particular, acetate orpropionate, nickel(II) complexes, such as nickel(II) acetylacetonate,dibromobis(triphenylphosphine)nickel(II) ordibromobis(bipyridine)nickel(II), or nickel(0) complexes, such asbis(1,5-cyclooctadiene)nickel(0) or[bis(diphenylphosphino)ethane]nickel(0).

Recourse may also be had to derivatives based on iron or on zinc,generally in the oxide or hydroxide form or in the form of salts, suchas halides, preferably chloride, nitrates and sulfates.

The amount of the metal element M represents less than 50 mol %,preferably less than 25 mol %, advantageously less than 10 mol %, withrespect to the number of moles of copper.

More preferably still, use is made of a catalyst in the form of acomplex with a butadienylphosphine comprising only copper.

A base, the function of which is to scavenge the leaving group, is alsoinvolved in the process of the invention.

The bases suitable for the process of the invention can be characterizedby their pKa, which is advantageously at least greater than or equal to2, preferably between 4 and 30.

The pKa is defined as the ionic dissociation constant of the acid/basepair when water is used as solvent. Reference may be made, for thechoice of a base having a pKa as defined by the invention, inter alia,to the Handbook of Chemistry and Physics, 66^(th) edition, pp. D-161 andD-162.

Mention may be made, among the bases which can be used, inter alia, ofinorganic bases, such as carbonates, hydrogencarbonates, phosphates orhydroxides of alkali metals, preferably sodium, potassium or cesium, orof alkaline earth metals, preferably calcium, barium or magnesium.

Recourse may also be had to alkali metal hydrides, preferably sodiumhydride, or to alkali metal alkoxides, preferably sodium alkoxides orpotassium alkoxides, and more preferably to sodium methoxide, ethoxideor tert-butoxide.

Organic bases, such as tertiary amines, are also suitable and mentionmay more particularly be made of triethylamine, tri(n-propyl)amine,tri(n-butyl)amine, methyldibutylamine, methyldicyclohexylamine,ethyldiisopropylamine, N,N-diethylcyclohexylamine, pyridine,4-(dimethylamino)pyridine, N-methylpiperidine, N-ethylpiperidine,N-(n-butyl)piperidine, 1,2-dimethylpiperidine, N-methylpyrrolidine and1,2-dimethyl-pyrrolidine.

The choice is preferably made, among the bases, of alkali metalcarbonates.

The amount of base employed is such that the ratio of the number ofmoles of base to the number of moles of the compound carrying theleaving group preferentially varies between 1 and 4, preferably in thevicinity of 2.

The coupling reaction, in particular arylation or vinylation oralkynylation reaction, carried out according to the invention isgenerally carried out in the presence of an organic solvent. Recourse ispreferably had to an organic solvent which does not react under theconditions of the reaction.

Recourse is preferably had, as types of solvents employed in the processof the invention, to a polar organic solvent and preferably a polaraprotic organic solvent.

Nonlimiting examples of solvents which can be employed in the process ofthe invention are chosen from:

-   -   linear or cyclic carboxamides, such as N,N-dimethylacetamide        (DMAC), N,N-diethylacetamide, dimethylformamide (DMF),        diethylformamide or 1-methyl-2-pyrrolidinone (NMP);    -   dimethyl sulfoxide (DMSO);    -   hexamethylphosphoramide (HMPT);    -   tetramethylurea;    -   nitro compounds, such as nitromethane, nitroethane,        1-nitropropane, 2-nitropropane and their mixtures, or        nitrobenzene;    -   aliphatic or aromatic nitriles, such as acetonitrile,        propionitrile, butanenitrile, isobutanenitrile, pentanenitrile,        2-methylglutaronitrile or adiponitrile;    -   tetramethylene sulfone (sulfolane);    -   organic carbonates, such as dimethyl carbonate, diisopropyl        carbonate or di(n-butyl) carbonate;    -   alkyl esters, such as ethyl acetate or isopropyl acetate;    -   halogenated or nonhalogenated aromatic hydrocarbons, such as        chlorobenzene or toluene;    -   ketones, such as acetone, methyl ethyl ketone, methyl isobutyl        ketone, cyclopentanone or cyclohexanone;    -   nitrogenous heterocycles, such as pyridine, picoline and        quinolines.

Use may also be made of a mixture of two or more solvents chosen inparticular from those listed above.

The preferred solvents are carboxamides, such as DMF, acetonitrile,DMSO, NMP and DMAC.

The amount of organic solvent to be employed is determined according tothe nature of the organic solvent chosen. It is determined so that theconcentration of the compound carrying the leaving group in the organicsolvent is preferably between 5% and 40% by weight.

According to an alternative form, the nucleophilic compound and/or thecompound carrying the leaving group can be used as solvent(s) for thereaction, in which case it is not necessary to add an additional solventto the reaction medium.

The coupling reaction, that is to say the reaction for the creation of aC—C or C-HE bond according to the process of the invention, is generallycarried out at a temperature which is advantageously situated between 0°C. and 200° C., preferably between 20° C. and 170° C. and morepreferably still between 25° C. and 140° C.

Said reaction is generally carried out at atmospheric pressure buthigher pressures, which can, for example, reach 10 bar, can also beused.

From a practical viewpoint, the reaction is simple to carry out.

The order in which the reactants are employed is not critical.Preferably, the copper/butadienylphosphine complex catalytic system, thenucleophilic compound, preferably of formula (Ia) to (Iv), the base, thecompound carrying the leaving group, preferably of formula (II), morepreferably of formula (IIa), (Iib) or (IIc), and optionally the organicsolvent are charged. The reaction medium is then brought to the desiredtemperature.

As mentioned above, it is possible, in an alternative form, to introducethe copper and at least one butadienylphosphine as ligand, in order toform the copper/butadienylphosphine complex in situ.

The progress of the reaction is monitored by following the disappearanceof the compound carrying the leaving group. At the end of the reaction,a product of the R-Q-R⁰ type is obtained, R, Q and R⁰ being as definedabove.

The compound obtained is recovered according to the conventionaltechniques used, in particular by crystallization from an organicsolvent.

Mention may in particular be made, as more specific examples of suchorganic solvents which can be used in the crystallization stage, ofaliphatic or aromatic hydrocarbons, which may or may not be halogenated,carboxamides and nitriles. Mention may in particular be made ofcyclohexane, toluene, dimethylformamide or acetonitrile.

Examples of the implementation of the invention are given below. Theseexamples are given by way of indication, without a limiting nature.

EXAMPLES Examples A Syntheses of the butadienylphosphines

The reactions are carried out under a pure and dry nitrogen atmosphere.40 ml (2 equivalents, 58.44 mmol) of n-butyllithium (n-BuLi; 1.6 M) areadded at −50° C. to a solution of 10 g (29.22 mmol) ofdimethyldiphenylphosphonium iodide [Ph₂P(CH₃)₂]⁺I⁻ in 300 ml ofanhydrous tetrahydrofuran (THF) and then the reaction mixture is broughtto −10° C. over one hour (yellow solution). 5.2 ml (1 equivalent, 29.22mmol) of chlorodiphenylphosphine are added at the same temperature. Thereaction mixture is left stirring in order to return to ambienttemperature over one hour (orange solution) and then one equivalent (ormore, if necessary) of the α,β-unsaturated aldehyde is added. Thereaction mixture is kept stirred at ambient temperature overnight. TheTHF is evaporated and then the residue is dissolved in dichloromethane.The organic phase obtained is subsequently washed three times withwater, dried over anhydrous magnesium sulfate (MgSO₄) and concentratedunder vacuum. The products are separated, with satisfactory yields, bychromatography on a silica or alumina column with a mixture ofhexane/dichloromethane eluant appropriate for each product.

Example A-1 Cinnamic butadienylphosphine Ph(C₄H₄)PPh₂

The general procedure described above was followed using 4 ml (29.22mmol) of cinnamaldehyde (trans). The two isomers are separated on analumina column with a mixture of hexane/dichloromethane (95/5) eluant.The reaction yield is 90% (E/Z=21/79).

Example A-1-1 Cinnamic butadienylphosphine (Z)-Ph(C₄H₄)PPh₂

Identification

Empirical formula: C₂₂H₁₉P

Molecular weight: 314.19

Melting point: 83-86° C. (hexane/dichloromethane)

³¹P {¹H} NMR (CDCl₃): δ=−28.08 (s, 1P)

¹H NMR (CDCl₃): δ=6.22 (dd, 1H, H₁, ²J_(H1P)=0.80 Hz); 6.60 (broad d,1H, H₄, ³J_(H4H3)=15.26 Hz); 6.97 (quintet, 1H, H₂, ³J_(H2H1)=11.25 Hz,³J_(H2H3)=11.15 Hz, ³J_(H2P)=22.47 Hz); 7.48 (m, 1H, H₃, ⁴J_(H3H1)=0.91Hz, ³J_(H3H4)=15.26 Hz, ⁴J_(H3P)=0.0023 Hz), 7.37-7.14 (m, 15H, 3Ph).

¹³C {¹H} NMR (CDCl₃): δ=143.96 (d, 1C, C₂, ²J_(CP)=20.47 Hz); 138.98 (d,2C, C_(ips), ¹J_(CipsP)=8.56 Hz); 136.87 (s, 1C, C₅); 136.31 (s, 1C,C₄); 132.68 (d, 4C, C_(o), ²J_(CoP)=18.98 Hz); 129.70 (d, 4C, C₃,³J_(C3P)=13.90 Hz); 128.60 (d, 4C, C_(m), ³J_(CmP)=6.58 Hz); 128.48 (s,2C, C_(p), ⁴J_(CpP)=5.12 Hz); 128.14 (s, 2C, C₆₋₁₀); 126.89 (s, 2C,C₇₋₉); 126.21 (d, 1C, C₁, ¹J_(C1P)=23.82 Hz).

IR (KBr): v (cm⁻¹)=3020 s, 3010 m, 1620 m, 1570 m, 1470 m, 1430 vs, 1300w, 1250 w, 1180 m, 1090 s, 1020 s, 980 s, 950 s, 690 vs.

Example A-1-2 Cinnamic butadienylphosphine (E)-Ph(C₄H₄)PPh₂

Identification

Empirical formula: C₂₂H₁₉P

Molecular weight: 314.19

³¹P {¹H} NMR (CDCl₃): δ=−11.32 (s, 1P)

¹H NMR (CDCl₃): δ=6.68 (m, 3H, 3CH); 7.45-7.26 (m, 15H, 3Ph); 7.79 (qdd,1H, CH)

¹³C {¹H} NMR (CDCl₃): δ=147.55 (d, 1C, C₃, ³J_(C3P)=3.52 Hz); 143.74 (d,1C, C₂, ²J_(CP)=27.98 Hz); 138.15 (d, 2C, C_(ips), ¹J_(CipsP)=9.56 Hz);136.87 (s, 1C, C₄); 134.39 (d, 2C, C₆₋₁₀, ⁶J_(CP)=1.46 Hz); 133.18 (d,4C, C_(o), ²J_(CoP)=19.02 Hz); 129.25 (d, 1C, C₁, ¹J_(C1P)=12.98 Hz);128.73 (S, 2C, C_(p)); 128.69 (d, 4C, C_(m), ³J_(CmP)=16.40 Hz); 126.70(s, 2C, C₇₋₉); 126.06 (s, 1C, C₈).

IR (KBr): v (cm⁻¹)=3040 s, 3010 s, 1640 s, 1580 s, 1470 s, 1430 vs, 1390w, 1190 s, 1115 s, 1090 m, 1030 m, 980 vs, 850 m, 720 s, 690 vs.

Example A-2 Crotonic butadienylphosphine CH₃(C₄H₄)PPh₂

The general procedure was followed using 2.4 ml (29.22 mmol) ofcrotonaldehyde (trans-2-butanal). The two isomers are separated on analumina column with a mixture of hexane/dichloromethane (97/3) eluant.The reaction yield is 80% (E/Z=25/75).

Example A-2-1 Crotonic butadienylphosphine (Z)—CH₃(C₄H₄)PPh₂

Identification:

Empirical formula: C₁₇H₁₇P

Molecular weight: 252.14

³¹P {¹H} NMR (CDCl₃): δ=−28.90 (s, 1P)

¹H NMR (CDCl₃): δ=1.65 (d, 3H, CH₃, ³J_(H3H4)=6.62 Hz); 5.73 (m, 1H,H₃); 5.94 (dd, 1H, H₁; ³J_(H1H2)=10.42 Hz, ³J_(H1P)=2.02 Hz); 6.79-6.69(m, 2H, H₂ and H₄); 7.62-7.11 (m, 10H, 2Ph).

¹³C {¹H} NMR (CDCl₃): δ=144.60 (d, 1C, C₂, ²J_(C2P)=21.59 Hz); 139.39(d, 2C, C_(ips), ¹J_(CipsP)=8.56 Hz); 134.53 (s, 1C, C₄); 132.66 (d, 4C,C_(o), ²J_(CoP)=18.61 Hz); 129.36 (d, 1C, C₁, ¹J_(C1P)=23.82 Hz); 128.53(d, 4C, C_(m), ³J_(CmP)=6.70 Hz); 128.37 (s, 2C, C_(p)); 126.18 (d, 1C,C₃, ³J_(C3P)=12.66 Hz); 18.47 (s, 1C, C₅).

IR (CCl₄): v (cm⁻¹)=3060 s, 3040 s, 3000 s, 2915 s, 1690 vs, 1580 s,1560 m, 1480 s, 1430 vs, 1370 m, 1300 w, 1100 m, 1030 s, 990 s, 950 s,930 m, 820 s, 730 vs, 690 vs.

Example A-2-2 Crotonic butadienylphosphine (E)-CH₃(C₄H₄)PPh₂

Identification

Empirical formula: C₁₇H₁₇P

Molecular weight: 252.14

³¹P {¹H} NMR (CDCl₃): δ=−12.58 (s, 1P)

¹H NMR (CDCl₃): δ=1.65 (d, 3H, CH₃, ⁴J_(H5H3)=1.51 Hz, ³J_(H5H4)=7.07Hz); 5.80 (sextet, 1H, H₃, ³J_(H3H2)=10.42 Hz, ⁴J_(H3H1)=6.82 Hz); 6.11(m, 2H, H₁ and H₄); 6.47 (m, 1H, H₂, ³J_(H2H1)=16.27 Hz, ⁴J_(H2H4)=9.60Hz, ³J_(H2P)=1.26 Hz); 7.35-7.14 (m, 10H, 2Ph).

¹³C {¹H} NMR (CDCl₃): δ=144.88 (d, 10, C₂, ²J_(CP)=31.35 Hz); 138.70 (d,2C, C_(ips), ¹J_(CP)=9.86 Hz); 132.94 (d, 4C, C_(o), ²J_(CP)=18.82 Hz);132.56 (s, 10, C₄); 132.39 (d, 10, C₁, ¹J_(CP)=17.31 Hz); 128.52 (s, 4C,C_(m)); 128.39 (s, 2C, C_(p)); 127.12 (d, 10, C₃, ³J_(CP)=9.41 Hz);18.22 (s, 10, C₅).

IR (CCl₄): v (cm⁻¹)=3060 s, 3040 s, 3000 s, 2900 s, 1640 vs, 1580 s,1475 s, 1430 vs, 1370 m, 1290 m, 1255 w, 1180 w, 1090 s, 1070 s, 1030vs, 990 vs, 930 w, 690 vs.

Examples B Preparations of the Copper/Butadienylphosphine complexes

The butadienylphosphine and the copper salt in the solid form aresuccessively introduced into a Schlenk tube purged three times viavacuum/nitrogen cycles. The reactor is purged under vacuum and thenagain filled with nitrogen. The solvent (acetonitrile) is then addedusing a syringe. The reactor is stirred at ambient temperature for 30min.

When the metal salt is liquid, it is added after the solvent using asyringe.

Example B-1 (Z)-Cinnamic phosphine/CuI complex

The general procedure described above was followed using 300 mg (0.954mmol) of (Z)-cinnamic butadienylphosphine (example A-1-1), 91 mg (0.477mmol) of cuprous iodide (CuI) and 10 ml of acetonitrile. The whiteprecipitate formed is filtered off and then recrystallized fromacetonitrile.

Yield: 383 mg (98%)

Identification:

Iododi{η-[(4-phenyl-1,3-butadienyl)diphenylphosphine]}copper complex

Empirical formula: C₄₄H₃₈CuIP₂

Molecular weight: 818.82

Melting point: 200-203° C. (acetonitrile)

³¹P {¹H} NMR (CDCl₃): δ=−21.86 (s, 1P)

¹H NMR (CDCl₃): δ=6.03 (dd, 1H, H₁, ³J_(H1H2)=11.83 Hz, ²J_(H1P)=6.36Hz); 6.47 (d, 1H, H₄, ³J_(H4H3)=15.26 Hz); 6.83 (quintet, 1H, H₂,³J_(H2P)=11.34 Hz); 7.13 (dd, 1H, H₃, ³J_(H2H3)=11.59 Hz); 7.33-7.18 (m,15H, 3Ph).

¹³C {¹H} NMR (CDCl₃): δ=143.70 (d, 1C, C₂, ²J_(CP)=4.09 Hz); 137.95 (s,1C, C₄); 136.30 (s, 1C, C₅); 134.16 (d, 2C, C_(i), ¹J_(CiP)=28.66 Hz);133.29 (d, 4C, C_(o), ²J_(CoP)=13.77 Hz); 129.55 (s, 10, C₈); 128.57 (d,4C, C_(m), ³J_(CmP)=8.05 Hz); 128.46 (s, 2C, C₉); 128.27 (s, 2C, C₆₋₁₀);127.60 (s, 2C, C₇₋₉); 126.15 (d, 10, C₃, ³J_(C3P)=13.40 Hz); 123.45 (d,10, C₁, ¹J_(C1P)=23.08 Hz).

FAB-MS (positive mode): m/z=691 [(Ph(C₄H₄)PPh₂)₂Cu]⁺, 377[(Ph(C₄H₄)PPh₂) Cu]⁺.

IR (KBr): v (cm⁻¹)=3066 vw, 3023 vw, 1618 m, 1595 w, 1576 m, 1478 m,1446 m, 1431 s, 1420 s, 1364 w, 1303 m, 1180 vw, 1156 m, 1096 m, 1066 m,987 s, 943 s, 755 m, 740 vs, 732 vs, 711 vs, 697 vs, 627 m, 616 w.

X-ray Structure:

Two phosphine-butadiene ligands are bonded to the copper solely via thedoublet of the phosphorus. The double bonds are not involved in thecoordination. The third ligand is iodine.

The values of the C1-C2 (1.343 Å) and C3-C4 (1.339 Å) bonds indicatethat the double bonds are not involved in the coordination. This isbecause these values correspond to that of a double bond,diphenylstyrylphosphine (table below).

Bond Length (Å) C2-C211 1.467 (2) C1-C2 1.339 (2) P1-C121 1.8385 (14)P1-C1 1.8412 (15) P1-C1 1.8140 (16)

Example B-2 (Z)-Crotonic phosphine/CuI complex

The general procedure described above was followed using 80 mg (0.317mmol) of (Z)-crotonic butadienylphosphine (example A-2-1), 30 mg (0.158mmol) of cuprous iodide (CuI) and 5 ml of acetonitrile. After treatment,the residue obtained was dissolved in a minimum amount ofdichloromethane and then precipitated from pentane.

Yield: 82 mg (75%).

Identification:

Empirical formula: C₃₄H₃₄CuIP₂

Molecular weight: 694.38

Melting point: 94-96° C. (pentane)

³¹P {¹H} NMR (CDCl₃): δ=−23.36 (s, 2P)

¹H NMR (CDCl₃): δ=1.61 (d, 6H, 2CH₃); 5.98-5.65 (m, 4H, 2H₁ and 2H₃);6.97-6.53 (m, 4H, 2H₂ and 2H₄); 7.35-7.15 (m, 120H, 4Ph).

¹³C {¹H} NMR (CDCl₃): δ=18.29 (s, 2C, 2C₅); 120.78 (d, 2C, 2C₁,¹J_(C1P)=21.6 Hz); 128.51 (d, 8C, 8C_(m), ³J_(CmP)=8.9 Hz); 129.35 (s,4C, 4C_(p)); 129.67 (s, 2C, 2C₃); 133.04 (d, 8C, 8C_(o), ²J_(CoP)=14.9Hz); 134.82 (d, 4C, ⁴C_(i), ¹J_(CiP)=25.7 Hz); 136.55 (s, 2C, 2C₄);144.74 (d, 2C, 2C₂, ²J_(C2P)=9.7 Hz)

FAB-MS (positive mode): m/z=567 [{CH₃(C₄H₄)PPh₂}₂Cu]⁺, 315[CH₃(C₄H₄)PPh₂Cu]⁺

IR (KBr): v (cm⁻¹)=3060 vw, 3000 vw, 2900 vw, 1640 m, 1560 w, 1540 w,1480 m, 1430 s, 1370 w, 1310 w, 1100 m, 1035 w, 990 s, 950 m, 930 m, 825w, 750 s, 730 w, 690 vs

Examples C Arylation reactions in the presence of thebutadienylphosphine and a copper salt

General Procedure

The copper salt, the butadienylphosphine (ligand), the nucleophile andthe base are successively introduced into a 35 ml Schlenk tube purgedthree times via vacuum/nitrogen cycles. The arylating agent and then thesolvent (acetonitrile) are then added using syringes. The reactionmixture is brought to the desired temperature and stirred at thistemperature for the duration shown.

Example C-1 Arylation of pyrazole

The general procedure described above (solvent: acetonitrile; reactiontemperature: 82° C.; duration of the reaction: 12 hours, or 30 hours inthe case of bromobenzene) was followed using 9.52 mg (0.05 mmol) ofcopper iodide CuI, 32 mg (0.1 mmol) of (Z)-cinnamic butadienylphosphineof example A-1-1, 68 mg (0.75 mmol) of pyrazole, 326 mg (1 mmol) ofcesium carbonate (Cs₂CO₃), 56 μl (0.5 mmol) of iodobenzene (or 53 μl ofbromobenzene) and 500 μl of acetonitrile. The oil obtained aftertreatment (dichloromethane/water extraction) was purified bychromatography on a silica column (eluant: dichloromethane/hexane50/50).

Yield: 70 mg of colorless oil (98%)

Identification:

¹H NMR (CDCl₃): δ=7.95-7.96 (dd, 1H, H₇); 7.71-7.75 (m, 3H,H_(2, 6, 9)); 7.47-7.50 (m, 2H, H_(3, 5)); 7.28-7.34 (m, 1H, H₄);6.49-6.50 (dd, 1H, H₈).

¹³C NMR (CDCl₃): δ=141.09 (C₉); 140.22 (C₁); 129.45 (C_(3, 5)); 126.75(C₇); 126.46 (C₄); 119.23 (C_(2, 6)); 107.61 (C₈)

IR (Kbr): v (cm⁻¹)=3142; 3050; 2924; 1600; 1520; 1500; 1393; 1332; 1198;1120; 1046; 936; 914; 755; 689; 654; 610; 515

GC/MS: rt=14.53 min, m/z=144

HRMS: 145.0766 (M+H). Theory: 145.0766

Example C-2 Arylation of 3,5-dimethylphenol

The general procedure (acetonitrile, 82° C., 12 hours or hours in thecase of bromobenzene) was followed using 9.52 mg (0.05 mmol) of copperiodide CuI, 31.4 mg (0.1 mmol) of (Z)-cinnamic butadienylphosphine ofexample A-1-1, 91.62 mg (0.75 mmol) of 3,5-dimethylphenol, 212 mg (1mmol) of potassium phosphate (K₃PO₄), 56 μl (0.5 mmol) of iodobenzene(53 μl of bromobenzene) and 500 μl of acetonitrile. The oil obtainedafter treatment (dichloromethane/water extraction) was purified bychromatography on a silica column (eluant: hexane).

Yield: 89 mg of colorless oil (90%)

Identification

¹H NMR (CDCl₃): δ=7.28-7.42 (m, 2H); 7.12-7.17 (m, 1H); 7.03-7.14 (m,2H); 6.79 (m, 1H); 6.69 (m, 2H); 2.33 (s, 6H, CH₃).

¹³C {¹H} NMR (CDCl₃): δ=157.50 (Cq); 157.22 (Cq); 139.61 (2 Cq); 129.70(2 CH); 125.04 (CH); 123.02 (CH); 118.89 (2 CH); 116.67 (2 CH); 21.35 (2CH₃)

GC/MS: rt=18.24 min, m/z=198

Rf: 0.22 (eluant: hexane)

Example C-3 Arylation of ethyl cyanoacetate

Preparation of 2-phenylethyl cyanoacetate

The general procedure (acetonitrile, 82° C., 12 hours with iodobenzene;30 hours in the case of bromobenzene) was followed using 9.52 mg (0.05mmol) of copper iodide CuI, 31.4 mg (0.1 mmol) of (Z)-cinnamicbutadienylphosphine of example A-1-1, 80 ml (0.75 mmol) of ethylcyanoacetate, 318 mg (1.5 mmol) of potassium phosphate (K₃PO₄), 56 μl(0.5 mmol) of iodobenzene (53 μl of bromobenzene) and 500 μl ofacetonitrile. The residue obtained after treatment(dichloromethane/water extraction) was purified by chromatography on asilica column (gradient: hexanes/CH₂Cl₂ 100:0 to 75:25).

Yield: 94%

¹H NMR (200 MHz, CDCl₃): δ (ppm)=7.37-7.45 (m, 5H); 4.71 (s, 1H); 4.25(q, ³J=7.1 Hz, 2H); 1.28 (t, ³J=7.1 Hz, 3H).

¹³C {¹H} NMR (50 MHz, CDCl₃): δ (ppm)=165.0 (Cq); 130.0 (Cq); 129.3 (2CH); 129.2 (CH); 127.9 (2 CH); 115.7 (CN); 63.3 (CH₂); 43.7 (CH); 13.9(CH₃)

GC/MS (EI): rt=15.24 min, m/z: 189

Rf: 0.22 (hexanes/CH₂Cl₂ 3:1)

Examples D Arylation reactions in the presence of the (Z)-cinnamicphosphine/CuI complex obtained in example B-1

General Procedure

The complex, the base, the nucleophile and the arylating agent aresuccessively introduced into a 35 ml Schlenk tube purged three times viavacuum/nitrogen cycles and then the solvent (acetonitrile) are thenadded using syringes. The tube is sealed under nitrogen pressure andthen stirred and brought to 82° C. for the time shown in the table.After cooling to ambient temperature, the mixture is diluted withdichloromethane (approximately 20 ml) and filtered through Celite(registered brand name). The precipitate is then washed several timeswith dichloromethane, the filtrate is washed with water, the organicphases are combined and dried over Na₂SO₄, filtered and concentratedunder vacuum, and then the crude products obtained are purified on achromatography column, elution being carried out with ahexane/dichloromethane mixture.

For a complete characterization of the products obtained, which are allknown, see the following papers: arylpyrazoles (Cristau, H. J., Cellier,P. P., Spindler, J.-F.; Taillefer, M., Chemistry, a European Journal,10, 2004, 5607, or European Journal of Organic Chemistry, 2004, 695),diaryl ethers (ibid, Organic Letters, 6, 2004, 913), vinylpyrazoles andvinyl aryl ethers (Ouali A., Renard B., Spindler, J.-F., Taillefer, M.,Chemistry, a European Journal, 2006, 20, 5301).

The reactions carried out are combined in the following table:

ArX NuH Time [h] Yield [%]

 4 98

 4 97

 4 98

10  91^([a])

24    70^([b]) ^([a])base: K₃PO₄. ^([b])DMF, 140° C.

Examples E Vinylation reactions in the presence of (Z)-cinnamicphosphine/CuI complex obtained in example B-1

The reactions combined in the following table were carried out accordingto the general procedure described in examples D.

vinylBr NuH Time [h] Yield [%]

 4 100

10  95

1. A process for the preparation of a butadienylphosphine of formula(1):

in which: R^(a) and R^(b), which are identical or different, eachrepresent a radical chosen independently from alkyl, aryl, heteroaryl,monoalkylamino, dialkylamino, alkoxy, aryloxy and heteroaryloxy; R¹, R²,R³, R⁴ and R⁵, which are identical or different, are chosenindependently from hydrogen, a hydrocarbon radical, an aryl radical anda heteroaryl radical; said process comprising the stages of: a) bringinga phosphonium halide of formula (2) into contact with a strong base in apolar aprotic solvent at low temperature, to result in the phosphoniumdiylide (3):

where R¹ is as defined above, Z and Z′ have definitions identical tothose of R^(a) and R^(b) defined above and X represents a halogen atomchosen from fluorine, chlorine, bromine and iodine; b) which diylide (3)is reacted, in the polar aprotic solvent medium, at a temperaturegenerally of between −70° C. and +10° C., with a halophosphine (4):

where R^(a) and R^(b) are as defined above and X′ represents a halogenatom chosen from fluorine, chlorine, bromine and iodine; to result inthe phosphonium ylide (5a), which undergoes a prototropic rearrangementto give the phosphonium ylide (5b):

where R^(a), R^(b), R¹, Z and Z′ are as defined above; c) the ylide (5b)then being brought together with an α,β-unsaturated carbonyl derivativeof formula (6):

in which R², R³, R⁴ and R⁵ are as defined above, to result, afterremoval of the solvent and optional purification, in thebutadienylphosphine (1).
 2. The process as claimed in claim 1, in whichthe R^(a) and R^(b) substituents of the butadienylphosphine of formula(1) are identical and each represent a radical chosen independently fromalkyl, aryl, heteroaryl, monoalkylamino, dialkylamino, alkoxy, aryloxyand heteroaryloxy.
 3. The process as claimed in claim 1, in which the R⁴and/or R⁵ substituents can be connected so as to form, with the carbonatom which carries them, a carbocyclic or heterocyclic group having from3 to 20 carbon atoms which is saturated, unsaturated, monocyclic orpolycyclic, in the latter case comprising two or three rings, it beingpossible for the adjacent rings to be aromatic in nature.
 4. The processas claimed in claim 1, in which the strong base is butyllithium.
 5. Theprocess as claimed in claim 1, in which the polar aprotic solvent istetrahydrofuran.
 6. The process as claimed in claim 1, in which thebutadienylphosphine of formula (1) obtained is of Z configuration or ofE configuration or is in the form of a mixture in all proportions of theZ and E configurations.
 7. The process as claimed in claim 1, in whichthe butadienylphosphine of formula (1) obtained exhibits the followingcharacteristics: R^(a) and R^(b) are identical and each represent aradical chosen from methyl, ethyl, propyl, butyl, phenyl, naphthyl,pyridyl or quinolyl; R¹ represents hydrogen, methyl, ethyl or propyl;R², R³ and R⁴, which are identical or different, are chosenindependently from hydrogen, methyl, ethyl and propyl; R⁵ is chosen fromhydrogen, methyl, ethyl, propyl, butyl, pentyl, phenyl, naphthyl,pyridyl and quinolyl.
 8. The process according to claim 1, in which thebutadienylphosphine of formula (1) obtained exhibits the followingcharacteristics: R^(a) and R^(b) each represent phenyl; R¹ representshydrogen; R², R³ and R⁴, which are identical or different, are chosenindependently from hydrogen, methyl, ethyl and propyl; R⁵ is chosen frommethyl, ethyl, propyl, phenyl, naphthyl, pyridyl and quinolyl.
 9. Theprocess as claimed in claim 1, in which the butadienylphosphine obtainedis (Z)-Ph(C₄H₄)PPh₂, (E)-Ph(C₄H₄)PPh₂, (Z)—CH₃(C₄H₄)PPh₂ or(E)-CH₃Ph(C₄H₄)PPh₂, where Ph represents phenyl.
 10. A complexcomprising copper and at least one butadienylphosphine of formula (1):

in which: R^(a) and R^(b), which are identical or different, eachrepresent a radical chosen independently from alkyl, aryl, heteroaryl,monoalkylamino, dialkylamino, alkoxy, aryloxy and heteroaryloxy; R¹, R²,R³, R⁴ and R⁵, which are identical or different, are chosenindependently from hydrogen, a hydrocarbon radical, an aryl radical anda heteroaryl radical.
 11. The complex as claimed in claim 10, in whichthe R^(a) and R^(b) substituents of the butadienylphosphine of formula(1) are identical and each represent a radical chosen independently fromalkyl, aryl, heteroaryl, monoalkylamino, dialkylamino, alkoxy, aryloxyand heteroaryloxy.
 12. The complex as claimed in claim 10, in which thebutadienylphosphine of formula (1) is of Z configuration or of Econfiguration or is in the form of a mixture in all proportions of the Zand E configurations.
 13. The complex as claimed in claim 10, in whichthe butadienylphosphine of formula (1) exhibits the followingcharacteristics: R^(a) and R^(b) are identical and each represent aradical chosen from methyl, ethyl, propyl, butyl, phenyl, naphthyl,pyridyl or quinolyl; R¹ represents hydrogen, methyl, ethyl or propyl;R², R³ and R⁴, which are identical or different, are chosenindependently from hydrogen, methyl, ethyl and propyl; R⁵ is chosen fromhydrogen, methyl, ethyl, propyl, butyl, pentyl, phenyl, naphthyl,pyridyl and quinolyl.
 14. The complex as claimed in claim 10, in whichthe butadienylphosphine of formula (1) exhibits the followingcharacteristics: R^(a) and R^(b) each represent phenyl; R¹ representshydrogen; R², R³ and R⁴, which are identical or different, are chosenindependently from hydrogen, methyl, ethyl and propyl; R⁵ is chosen frommethyl, ethyl, propyl, phenyl, naphthyl, pyridyl and quinolyl.
 15. Thecomplex as claimed in claim 10, in which the butadienylphosphine offormula (1) is (Z)-Ph(C₄H₄)PPh₂, (E)-Ph(C₄H₄)PPh₂, (Z)—CH₃(C₄H₄)PPh₂ or(E)-CH₃Ph(C₄H₄)PPh₂, where Ph represents phenyl.
 16. The complex asclaimed in claim 10, which is thephenylbutadienyldiphenylphosphine/copper iodide monomer complex[Ph-CH═CH—CH═CH—PPh₂]₂CuI(iododi{η-[(4-phenyl-1,3-butadienyl)diphenylphosphine]}copper complex),where Ph represents the phenyl radical.
 17. The complex as claimed inclaim 10, which is the methylbutadienyldiphenylphosphine/copper iodidemonomer complex [CH₃—CH═CH—CH═CH—PPh₂]₂CuI(iododi{η-[(4-methyl-1,3-butadienyl)diphenylphosphine]}copper complex),where Ph represents the phenyl radical.
 18. A process for the creationof a carbon-carbon (C—C) bond or of a carbon-heteroatom (C-HE) bond byreacting a compound carrying a leaving group with a nucleophiliccompound carrying a carbon atom or a heteroatom (HE) capable ofreplacing the leaving group, thus creating a C—C or C-HE bond, in whichprocess the reaction is carried out in the presence of an effectiveamount of a catalytic system comprising at least onecopper/butadienylphosphine complex.
 19. The process as claimed in claim18, in which the copper/butadienylphosphine is a complex of the formula(1):

in which: R^(a) and R^(b), which are identical or different, eachrepresent a radical chosen independently from alkyl, aryl, heteroaryl,monoalkylamino, dialkylamino, alkoxy, aryloxy and heteroaryloxy; R¹, R²,R³, R⁴ and R⁵, which are identical or different, are chosenindependently from hydrogen, a hydrocarbon radical, an aryl radical anda heteroaryl radical.
 20. The process as claimed in claim 19, in whichthe compound carrying a leaving group is a compound comprising a doublebond or a triple bond in the α position with respect to said leavinggroup or an aromatic compound.
 21. The process as claimed in claim 19,in which the nucleophilic compound is an acyclic, cyclic or polycyclichydrocarbon organic compound comprising at least one atom carrying afree doublet, which may or may not comprise a charge, and or comprise acarbon atom which can donate its electron pair.
 22. The process asclaimed in claim 19, in which the ratio between the number of moles ofthe compound carrying the leaving group to the number of moles of thenucleophilic compound generally varies between 0.1 and 2.0.
 23. Theprocess as claimed in claim 19, in which the total amount ofcopper/butadienylphosphine complex catalyst, expressed by the molarratio of the number of moles of complex, expressed as copper, to thenumber of moles of compound carrying a leaving group, generally variesbetween 0.001 and 0.5.
 24. The process as claimed in claim 19, in whicha base having a pKa of between 4 and 30 is involved.
 25. The process asclaimed in claim 19, in which a base chosen from carbonates,hydrogencarbonates, phosphates or hydroxides of alkali metals or ofalkaline earth metals, alkali metal hydrides, alkali metal alkoxides andtertiary amines is involved.
 26. The process as claimed in claim 19,which is carried out in the presence of a polar organic solvent.
 27. Theprocess as claimed in claim 19, in which the nucleophilic compoundand/or the compound carrying the leaving group is (are) used assolvent(s) for the reaction.
 28. The process as claimed in claim 19, inwhich the copper/butadienylphosphine complex is prepared in situ.